Substituted pyridines as apoptosis signal-regulating kinase 1 inhibitors

ABSTRACT

The present invention discloses compounds of Formula (I), and pharmaceutically acceptable salts and esters thereof: 
                         
which inhibit the Apoptosis signal-regulating kinase 1 (ASK-1), which associated with autoimmune disorders, neurodegenerative disorders, inflammatory diseases, chronic kidney disease, cardiovascular disease. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from ASK-1 related disease. The invention also relates to methods of treating an ASK-1 related disease in a subject by administering a pharmaceutical composition comprising the compounds of the present invention. The present invention specifically relates to methods of treating ASK-1 associated with hepatic steatosis, including non-alcoholic fatty liver disease (NAFLD) and non-alcohol steatohepatitis disease (NASH).

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.62/823,195, filed on Mar. 25, 2019. The entire teachings of the aboveapplication are incorporated herein by reference.

TECHNICAL FIELD

The present invention relates generally to compounds and pharmaceuticalcompositions useful as ASK-1 inhibitors. Specifically, the presentinvention relates to compounds useful as inhibitors of ASK-1 and methodsfor their preparation and use.

BACKGROUND OF THE INVENTION

Apoptosis signal-regulating kinase 1 (ASK-1) is a member of themitogen-activated protein kinase kinase kinase (MAPKKK, MAP3K) family,which when activated phosphorylates downstream MAP kinase kinases(MAPKK, MAP2K), which in turn activate MAP kinases (MAPK). MAPKs elicita response by phosphorylating cellular substrates, thus regulating theactivity of transcription factors that ultimately control geneexpression. Specifically ASK-1, also known as MAPKKK5, phosphorylatesMAPKK4/MAPKK7 or MAPKK3/MAPKK6, which subsequently phosphorylates andactivates the c-Jun N-terminal protein kinase (JNK) and p38 MAPKs,respectively (H. Ichijo, et al., Cell Comm. Signal 2009, 7, 1-10; K.Takeda, et al., Annu. Rev. Pharmacol. Toxicol. 2008, 48, 199-225; H.Nagai, et al., J Biochem. Mol. Biol. 2007, 40, 1-6). Activation of theJNK and p38 pathways triggers a downstream stress response such asapoptosis, inflammation, or differentiation (H. Ichijo, et al., Science1997, 275, 90-94; K. Takeda, et al., J. Biol. Chem. 2000, 275,9805-9813; K. Tobiume, et al., EMBO Rep. 2001, 2, 222-228; K. Sayama etal., J. Biol. Chem. 2001, 276, 999-1004).

The activity of ASK-1 is regulated by thioredoxin (Trx), which binds tothe N-terminal end of ASK-1 (M. Saitoh, et al., EMBO J. 1998, 17,2596-2606). ASK-1 is activated succeeding autophosphorylation at Thr838in response to environmental stimuli including oxidative stress,lipopolysaccharides (LPS), reactive oxygen species (ROS), endoplasmicreticulum (ER) stress, an increase in cellular calcium ionconcentrations, Fas ligand, and various cytokines such as tumor necrosisfactor (TNF) (H. Nishitoh, et al., Genes Dev. 2002, 16, 1345-1355; K.Takeda, et al., EMBO Rep. 2004, 5, 161-166; A. Matsuzawa, et al., Nat.Immunol. 2005, 6, 587-592).

ASK-1 has been associated with autoimmune disorders, neurodegenerativedisorders, inflammatory diseases, chronic kidney disease, cardiovasculardisease, metabolic disorders, and acute and chronic liver diseases (R.Hayakawa, et al., Proc. Jpn. Acad., Ser. B 2012, 88, 434-453).

More specifically, ASK-1 has been associated with hepatic steatosis,including non-alcoholic fatty liver disease (NAFLD) and non-alcoholsteatohepatitis (NASH). In a mouse model, high fat diets have causedinduction of hepatic steatosis, ultimately causing fat accumulation andfatty acid oxidation. This led to the generation of ROS which causedhepatocyte dysfunction and death (S. K. Mantena, et al., Free Radic.Biol. Med. 2008, 44, 1259-1272; S. K. Mantena, et al., Biochem. J. 2009,417, 183-193). Moreover, TNF was shown to be critical for apoptosis ofhepatocytes through the ASK-1-JNK pathway, and TNF deficient mice showedreduced hepatic steatosis and fibrosis (W. Zhang, et al., Biochem.Biophys. Res. Commun. 2010, 391, 1731-1736).

Small molecule compounds which act as ASK-1 inhibitors have beendisclosed in the following publications: WO 2008/016131, WO 2009/027283,WO 2009/0318425, WO 2009/123986, US 2009/0318425, WO 2011/041293, WO2011/097079, US 2011/0009410, J. Med. Chem. 2011, 54, 2680-2686, Bioorg.Med. Chem. 2011, 19, 486-489, WO 2012/003387, WO 2012/011548, WO2012/080735, Y. Terao, et al., Bioorg. Med. Chem. Lett. 2012, 22,7326-7329, WO 2013/112741, Eur. J. Med. Chem. 2013, 16, 104-115, US2014/0018370, WO 2014/100541, WO 2015/095059, Bioorg. Med. Chem. Lett.2015, 23, 2489-2497, WO 2016/049069, WO 2016/049070, WO 2016/106384, ACSMed. Chem. Lett. 2017, 8, 316-320, WO 2018/090869, WO 2018/133865, WO2018/133866, WO 2018/148204, WO 2018/149284, WO 2018/151830, WO2018/157277, WO 2018/157856, WO 2018/157857, WO 2018/160406, WO2018/169742, WO 2018/183122, WO 2018/187506, WO 2018/218042, WO2018/218044, WO 2018/218051, WO 2018/233553, Bioorg. Med. Chem. Lett.2018, 28, 400-404, Eur. J. Med. Chem. 2018, 145, 606-621.

There is a need for the development of ASK-1 inhibitors for thetreatment and prevention of disease. The present invention hasidentified compounds which inhibit ASK-1 as well as methods of usingthese compounds to treat disease.

SUMMARY OF THE INVENTION

In one aspect, the invention provides compounds represented by FormulaI, or a pharmaceutically acceptable salt or ester thereof:

wherein:one of X¹ and X² is C(R⁶), and the other is C(R⁶) or N;X³ is C(R⁷) or N, wherein R⁷ is selected from the group consisting ofhydrogen, optionally substituted —C₁-C₈ alkyl, optionally substituted—C₁-C₈ alkoxy and halo;A is optionally substituted heterocycloalkyl or optionally substitutedheteroaryl which is fused with the 1,2,4-triazolyl ring;R² and R⁶ are each independently selected from the group consisting of:

1) Hydrogen;

2) Halogen;

3) —NO₂;

4) Cyano;

5) Substituted or unsubstituted —C₁-C₈ alkyl;

6) Substituted or unsubstituted —C₂-C₈ alkenyl;

7) Substituted or unsubstituted —C₂-C₈ alkynyl;

8) Substituted or unsubstituted —C₃-C₈ cycloalkyl;

9) Substituted or unsubstituted aryl;

10) Substituted or unsubstituted arylalkyl;

11) Substituted or unsubstituted 3- to 8-membered heterocycloalkyl;

12) Substituted or unsubstituted heteroaryl;

13) Substituted or unsubstituted heteroarylalkyl;

14) —N(R⁴)(R⁵);

15) —S(O)₂N(R⁴)(R⁵);

16) —N(R⁴)C(O)R⁵; and

17) —N(R⁴)S(O)₂R⁵;

R³ is selected from the group consisting of:

1) Hydrogen;

2) Substituted or unsubstituted —C₁-C₈ alkyl;

3) Substituted or unsubstituted —C₂-C₈ alkenyl;

4) Substituted or unsubstituted —C₂-C₈ alkynyl;

5) Substituted or unsubstituted —C₃-C₈ cycloalkyl;

6) Substituted or unsubstituted aryl;

7) Substituted or unsubstituted arylalkyl;

8) Substituted or unsubstituted 3- to 8-membered heterocycloalkyl;

9) Substituted or unsubstituted heteroaryl;

10) Substituted or unsubstituted heteroarylalkyl;

11) —C(O)R⁴;

12) —C(O)OR⁴;

13) —C(O)N(R⁴)(R⁵); and

14) —SO₂R⁴;

R⁴ and R⁵ are independently hydrogen, —C₁-C₈ alkyl, —C₁-C₈ alkenyl,—C₁-C₈ alkynyl, —C₃-C₈ cycloalkyl, aryl, arylalkyl, heterocycloalkyl,heteroaryl, and heteroarylalkyl, wherein the —C₁-C₈ alkyl, —C₁-C₈alkenyl, —C₁-C₈ alkynyl, —C₃-C₈ cycloalkyl, aryl, arylalkyl,heterocycloalkyl, heteroaryl, and heteroarylalkyl is optionallysubstituted with 1-3 substituents independently selected from halo, oxo,alkyl, —C₃-C₈ cycloalkyl, alkylamino, dialkylamino, alkyl-C(O)—NH—,aryl-C(O)NH—, heteroaryl-C(O)NH—, heterocycloalkyl,heterocycloalkyl-C(O)—, —OH, —CN, alkoxy, —CF₃, aryl, and heteroaryl; orR⁴ and R⁵ are taken together with the nitrogen atom to which they areattached to form an optionally substituted heterocycloalkyl;

R⁸ and R⁹ are each independently selected from the group consisting ofhydrogen, hydroxyl, and optionally substituted —C₁-C₈ alkyl;alternatively, R⁸ and R⁹ are taken together with the carbon atom towhich they are attached to form C(O), spiro-C₃-C₈ cycloalkyl, orspiro-3- to 8-membered heterocycloalkyl;

R¹⁰ and R¹¹ are each independently selected from the group consisting ofhydrogen, halo, and optionally substituted —C₁-C₈ alkyl; and

n is 0, 1 or 2; preferably n is 0 or 1.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundor combination of compounds of the present invention, or apharmaceutically acceptable salt form, stereoisomer, solvate, hydrate orcombination thereof, in combination with a pharmaceutically acceptablecarrier or excipient.

In another embodiment, the present invention provides a method for theprevention or treatment of an ASK-1 mediated disease or condition. Themethod comprises administering a therapeutically effective amount of acompound of Formula (I) to a subject in need thereof. The presentinvention also provides the use of a compound of Formula (I) for thepreparation of a medicament for the prevention or treatment of an ASK-1mediated disease or condition. Such diseases include autoimmunedisorders, neurodegenerative disorders, inflammatory diseases, chronickidney disease, cardiovascular disease, metabolic disorders, and acuteand chronic liver diseases.

DETAILED DESCRIPTION OF THE INVENTION

A first embodiment of the invention is a compound represented by FormulaI as described above, or a pharmaceutically acceptable salt or esterthereof.

In certain embodiments of the compounds of the invention, R² is hydrogenor halogen.

In certain embodiments of the compounds of the invention, n is 0 or 1,preferably 1.

In certain embodiments of the compounds of the invention, R² is hydrogenand n is 0 or 1.

In certain embodiments of the compounds of the invention, R⁸ ishydrogen.

In certain embodiments of the compounds of the invention, R⁹ ishydrogen.

In certain embodiments of the compounds of the invention, R⁸ and R⁹ areboth hydrogen.

In certain embodiments of the compounds of the invention, R¹⁰ ishydrogen, halogen or optionally substituted methyl.

In certain embodiments of the compounds of the invention, R¹¹ ishydrogen, halogen or optionally substituted methyl.

In certain embodiments of the compounds of the invention, R¹⁰ and R¹¹are both hydrogen.

In certain embodiments of the compounds of the invention, R⁸, R⁹, R¹⁰and R¹¹ are all hydrogen.

In certain embodiments of the compounds of the invention, R³ is

wherein R⁴ is selected from the groups below:

wherein each of the above shown groups is optionally substituted.

In certain embodiments of the compounds of the invention, R³ is

wherein R⁴ and R⁵ are taken together with the nitrogen atom to whichthey are they attached to form a heterocycloalkyl which is selected fromthe groups below:

wherein each of the above shown groups is optionally substituted.

In certain embodiments of the compounds of the invention, R³ is

wherein R⁴ is selected from the groups below:

wherein each of the above shown groups is optionally substituted.

In certain embodiments of the compounds of the invention, R³ is selectedfrom the groups below:

wherein each of these groups is optionally substituted.

In certain embodiments of the compounds of the invention, X³ is selectedfrom C—H, C—F, C—OMe, and N.

In certain embodiments of the compounds of the invention,

is selected from the groups below:

wherein each of the above shown groups is optionally substituted.

In certain embodiments, the invention provides compounds of FormulaIa-1, Ia-2, Ib-1, Ib-2, Ic-1, Ic-2, and Ie, and pharmaceuticallyacceptable salts and esters thereof:

wherein A, R², R³, R⁸, R⁹, R¹⁰, R¹¹, X¹, X², X³, and n are as previouslydefined.

In certain embodiments, the compound of Formula I is represented byFormula II or a pharmaceutically acceptable salt or ester thereof:

wherein A, R², R³, R⁸, R⁹, R¹⁰, R¹¹, X², X³ and n are as previouslydefined.

In certain embodiments, the compound of Formula I is represented byFormula III or a pharmaceutically acceptable salt or ester thereof:

wherein A, R², R³, R⁸, R⁹, R¹⁰, R¹¹, X³ and n are as previously defined.

In certain embodiments, the compound of Formula I is represented byFormula IV or a pharmaceutically acceptable salt or ester thereof:

wherein A, R³, R⁸, R⁹, R¹⁰, R¹¹, X³ and n are as previously defined.

In certain embodiments, the compound of Formula I is represented byFormula V or a pharmaceutically acceptable salt or ester thereof:

wherein A, R³, X³, and n are as previously defined.

In certain embodiments, the present invention relates to compounds ofFormula I, Ia-1, Ia-2, Ib-1, Ib-2, Ic-1, Ic-2, Ie, II, III, IV, and V,and pharmaceutically acceptable salts and esters thereof, wherein

is selected from the groups below:

wherein each of the above shown groups is optionally substituted.

In certain embodiments, the compound of Formula I is represented byFormula VI or a pharmaceutically acceptable salt or ester thereof:

wherein R³, X³, and n are as previously defined.

Representative compounds of the invention include, but are not limitedto, the following compounds (compound 1 to compound 96 in Table 1) andpharmaceutically acceptable salts thereof.

TABLE 1 Compound Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

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28

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96

In certain embodiments, the compound of Formula I is represented byFormula VII or a pharmaceutically acceptable salt or ester thereof:

wherein R³, X³, and n are as previously defined.

Representative compounds of the invention include, but are not limitedto, the following compounds (compound 97 to compound 192 in Table 2) andpharmaceutically acceptable salts thereof.

TABLE 2 Structure Compound 97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

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186

187

188

189

190

191

192

In certain embodiments, the compound of Formula I is represented byFormula VIII or a pharmaceutically acceptable salt or ester thereof:

wherein R³, X³, and n are as previously defined.

Representative compounds of the invention include, but are not limitedto, the following compounds (compound 193 to compound 288 in Table 3)and pharmaceutically acceptable salts thereof.

TABLE 3 Compound Structure 193

194

195

196

197

198

199

200

201

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283

284

285

286

287

288

In certain embodiments, the compound of Formula I is represented byFormula IX or a pharmaceutically acceptable salt or ester thereof:

wherein R³, X³, and n are as previously defined.

Representative compounds of the invention include, but are not limitedto, the following compounds (compound 289 to compound 384 in Table 4),and pharmaceutically acceptable salts thereof.

TABLE 4 Compound Structure 289

290

291

292

293

294

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296

297

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381

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383

384

In certain embodiments, the compound of Formula I is represented byFormula X or a pharmaceutically acceptable salt or ester thereof:

wherein R³, X³, and n are as previously defined.

Representative compounds of the invention include, but are not limitedto, the following compounds (compound 385 to compound 480 in Table 5)and pharmaceutically acceptable salts thereof.

TABLE 5 Compound Structure 385

386

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389

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391

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475

476

477

478

479

480

In certain embodiments, the present invention provides a method for thetreatment of an ASK-1 mediated disease or condition. The methodcomprises administering a therapeutically effective amount of a compoundof Formula (I). The present invention also provides the use of acompound of Formula (I) for the preparation of a medicament for thetreatment of an ASK-1 mediated disease or condition.

In certain embodiments, the ASK-1 mediated disease or condition is anautoimmune disorder, a neurodegenerative disorder, an inflammatorydisease, chronic kidney disease, renal disease, cardiovascular disease,a metabolic disease, or an acute or chronic liver disease.

In certain embodiments, the chronic liver disease is primary biliarycirrhosis (PBC), cerebrotendinous xanthomatosis (CTX), primarysclerosing cholangitis (PSC), drug induced cholestasis, intrahepaticcholestasis of pregnancy, parenteral nutrition associated cholestasis(PNAC), bacterial overgrowth or sepsis associated cholestasis,autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease,nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis(NASH), liver transplant associated graft versus host disease, livingdonor transplant liver regeneration, congenital hepatic fibrosis,choledocholithiasis, granulomatous liver disease, intra- or extrahepaticmalignancy, Sjogren's syndrome, Sarcoidosis, Wilson's disease, Gaucher'sdisease, hemochromatosis, or alpha 1-antitrypsin deficiency. In certainembodiments, the gastrointestinal disease is inflammatory bowel disease(IBD) (including Crohn's disease and ulcerative colitis), irritablebowel syndrome (IBS), bacterial overgrowth, malabsorption,post-radiation colitis, or microscopic colitis.

In certain embodiments, the renal disease is diabetic nephropathy, focalsegmental glomerulosclerosis (FSGS), hypertensive nephrosclerosis,chronic glomerulonephritis, chronic transplant glomerulopathy, chronicinterstitial nephritis, or polycystic kidney disease.

In certain embodiments, the cardiovascular disease is atherosclerosis,arteriosclerosis, reperfusion/ischemia in stroke, cardiac hypertrophy,respiratory diseases, heart attacks, myocardial ischemia.

In certain embodiments, the metabolic disease is insulin resistance,Type I and Type II diabetes, or obesity.

In certain embodiments, the chronic kidney disease is polycystic kidneydisease, pyelonephritis, kidney fibrosis and glomerulonephritis.

Yet a further aspect of the present invention is a process of making anyof the compounds delineated herein employing any of the synthetic meansdelineated herein.

Definitions

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

The term “alkyl” as used herein, refers to saturated, straight- orbranched-chain hydrocarbon radicals. “C₁-C₃ alkyl,” “C₁-C₆ alkyl,”“C₁-C₁₀ alkyl” C₂-C₄ alkyl,” or “C₃-C₆ alkyl,” refer to alkyl groupscontaining from one to three, one to six, one to ten carbon atoms, 2 to4 and 3 to 6 carbon atoms respectively. Examples of C₁-C₈ alkyl radicalsinclude, but are not limited to, methyl, ethyl, propyl, isopropyl,n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl and octyl radicals.

The term “alkenyl” as used herein, refers to straight- or branched-chainhydrocarbon radicals having at least one carbon-carbon double bond bythe removal of a single hydrogen atom. “C₂-C₁₀ alkenyl,” “C₂-C₈alkenyl,” “C₂-C₄ alkenyl,” or “C₃-C₆ alkenyl,” refer to alkenyl groupscontaining from two to ten, two to eight, two to four or three to sixcarbon atoms respectively. Alkenyl groups include, but are not limitedto, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl,heptenyl, octenyl, and the like.

The term “alkynyl” as used herein, refers to straight- or branched-chainhydrocarbon radicals having at least one carbon-carbon triple bond bythe removal of a single hydrogen atom. “C₂-C₁₀ alkynyl,” “C₂-C₈alkynyl,” “C₂-C₄ alkynyl,” or “C₃-C₆ alkynyl,” refer to alkynyl groupscontaining from two to ten, two to eight, two to four or three to sixcarbon atoms respectively. Representative alkynyl groups include, butare not limited to, for example, ethynyl, 1-propynyl, 1-butynyl,heptynyl, octynyl, and the like.

The term “cycloalkyl”, as used herein, refers to a monocyclic orpolycyclic saturated carbocyclic ring or a bi- or tri-cyclic groupfused, bridged or spiro system, and the carbon atoms may be optionallyoxo-substituted or optionally substituted with exocyclic olefinic,iminic or oximic double bond. Preferred cycloalkyl groups include C₃-C₁₂cycloalkyl, C₃-C₆ cycloalkyl, C₃-C₈ cycloalkyl and C₄-C₇ cycloalkyl.Examples of C₃-C₁₂ cycloalkyl include, but not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclooctyl,4-methylene-cyclohexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.0]hexyl,spiro[2.5]octyl, 3-methylenebicyclo[3.2.1]octyl, spiro[4.4]nonanyl, andthe like.

The term “cycloalkenyl”, as used herein, refers to monocyclic orpolycyclic carbocyclic ring or a bi- or tri-cyclic group fused, bridgedor spiro system having at least one carbon-carbon double bond and thecarbon atoms may be optionally oxo-substituted or optionally substitutedwith exocyclic olefinic, iminic or oximic double bond. Preferredcycloalkenyl groups include C₃-C₁₂ cycloalkenyl, C₃-C₈ cycloalkenyl orC₅-C₇ cycloalkenyl groups. Examples of C₃-C₁₂ cycloalkenyl include, butnot limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl,cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo[2.2.1]hept-2-enyl,bicyclo[3.1.0]hex-2-enyl, spiro[2.5]oct-4-enyl, spiro[4.4]non-1-enyl,bicyclo[4.2.1]non-3-en-9-yl, and the like.

The term “aryl,” as used herein, refers to a mono- or polycycliccarbocyclic ring system comprising at least one aromatic ring,including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl,indanyl, and indenyl. A polycyclic aryl is a polycyclic ring system thatcomprises at least one aromatic ring. Polycyclic aryls can comprisefused rings, covalently attached rings or a combination thereof.

The term “heteroaryl,” as used herein, refers to a mono- or polycyclicaromatic radical having one or more ring atom selected from S, O and N;and the remaining ring atoms are carbon, wherein any N or S containedwithin the ring may be optionally oxidized. Heteroaryl includes, but isnot limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl,imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl,thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl,benzoxazolyl, quinoxalinyl. A polycyclic heteroaryl can comprise fusedrings, covalently attached rings or a combination thereof.

In accordance with the invention, aromatic groups can be substituted orunsubstituted. The term “bicyclic aryl” or “bicyclic heteroaryl” refersto a ring system consisting of two rings wherein at least one ring isaromatic; and the two rings can be fused or covalently attached.

As used herein, the term “arylalkyl” means a functional group wherein analkylene chain is attached to an aryl group, e.g., —CH₂CH₂-phenyl. Theterm “substituted arylalkyl” means an arylalkyl functional group inwhich the aryl group is substituted. Similarly, the term“heteroarylalkyl” means a functional group wherein an alkylene chain isattached to a heteroaryl group. The term “substituted heteroarylalkyl”means a heteroarylalkyl functional group in which the heteroaryl groupis substituted.

The term “alkylene” as used herein, refers to a diradical of a branchedor unbranched saturated hydrocarbon chain, typically having from 1 to 20carbon atoms (e.g. 1-10 carbon atoms, or 1, 2, 3, 4, 5, or 6 carbonatoms). This term is exemplified by groups such as methylene (—CH₂—),ethylene (—CH₂CH₂—), the propylene isomers (e.g., —CH₂CH₂CH₂— and—CH(CH₃)CH₂—), and the like.

The term “substituted” as used herein, refers to independent replacementof one, two, or three or more of the hydrogen atoms thereon withsubstituents including, but not limited to, deuterium, —F, —Cl, —Br, —I,—OH, protected hydroxy, —NO₂, —CN, —NH₂, N₃, protected amino, alkoxy,thioalkoxy, oxo, C₁-C₁₂-alkyl, C₂-C₁₂-alkenyl, C₂-C₁₂-alkynyl,-halo-C₁-C₁₂-alkyl, -halo-C₂-C₁₂-alkenyl, -halo-C₂-C₁₂-alkynyl,-halo-C₃-C₁₂-cycloalkyl, —NH—C₁-C₁₂-alkyl, —NH—C₂-C₁₂-alkenyl,—NH—C₂-C₁₂-alkynyl, —NH—C₃-C₁₂-cycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino,—O—C₁-C₁₂-alkyl, —O—C₂-C₁₂-alkenyl, —O—C₂-C₁₂-alkynyl,—O—C₃-C₁₂-cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl,—C(O)—C₁-C₁₂-alkyl, —C(O)—C₂-C₁₂-alkenyl, —C(O)—C₂-C₁₂-alkynyl,—C(O)—C₃-C₁₂-cycloalkyl, —C(O)-aryl, —C(O)-heteroaryl,—C(O)-heterocycloalkyl, —CONH₂, —CONH—C₁-C₁₂-alkyl,—CONH—C₂-C₁₂-alkenyl, —CONH—C₂-C₁₂-alkynyl, —CONH—C₃-C₁₂-cycloalkyl,—CONH-aryl, —CONH— heteroaryl, —CONH-heterocycloalkyl,—OCO₂—C₁-C₁₂-alkyl, —OCO₂—C₂-C₁₂-alkenyl, —OCO₂—C₂-C₁₂-alkynyl,—OCO₂—C₃-C₁₂-cycloalkyl, —OCO₂-aryl, —OCO₂-heteroaryl,—OCO₂-heterocycloalkyl, —OCONH₂, —OCONH—C₁-C₁₂-alkyl,—OCONH—C₂-C₁₂-alkenyl, —OCONH—C₂-C₁₂-alkynyl, —OCONH—C₃-C₁₂-cycloalkyl,—OCONH— aryl, —OCONH— heteroaryl, —OCONH— heterocycloalkyl,—NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₁₂-alkenyl, —NHC(O)—C₂-C₁₂-alkynyl,—NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl,—NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl,—NHCO₂—C₂-C₁₂-alkynyl, —NHCO₂—C₃-C₁₂-cycloalkyl, —NHCO₂— aryl, —NHCO₂—heteroaryl, —NHCO₂— heterocycloalkyl, —NHC(O)NH₂,—NHC(O)NH—C₁-C₁₂-alkyl, —NHC(O)NH—C₂-C₁₂-alkenyl,—NHC(O)NH—C₂-C₁₂-alkynyl, —NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl,—NHC(O)NH-heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S)NH₂,—NHC(S)NH—C₁-C₁₂-alkyl, —NHC(S)NH—C₂-C₁₂-alkenyl,—NHC(S)NH—C₂-C₁₂-alkynyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,—NHC(NH)NH—C₁-C₁₂-alkyl, —NHC(NH)NH—C₂-C₁₂-alkenyl,—NHC(NH)NH—C₂-C₁₂-alkynyl, —NHC(NH)NH—C₃-C₁₂-cycloalkyl,—NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl,—NHC(NH)—C₁-C₁₂-alkyl, —NHC(NH)—C₂-C₁₂-alkenyl, —NHC(NH)—C₂-C₁₂-alkynyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₁₂-alkenyl, —C(NH)NH—C₂-C₁₂-alkynyl,—C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NH-heterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₁₂-alkenyl,—S(O)—C₂-C₁₂-alkynyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl —SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₂-C₁₂-alkynyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH— aryl, —SO₂NH— heteroaryl, —SO₂NH— heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₁₂-alkenyl, —NHSO₂—C₂-C₁₂-alkynyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl, —NHSO₂—heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl, -heteroaryl,-heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH,—S—C₁-C₁₂-alkyl, —S—C₂-C₁₂-alkenyl, —S—C₂-C₁₂-alkynyl,—S—C₃-C₁₂-cycloalkyl, —S-aryl, —S-heteroaryl, —S-heterocycloalkyl,methylthiomethyl, or -L′-R′, wherein L′ is C₁-C₆alkylene,C₂-C₆alkenylene or C₂-C₆alkynylene, and R′ is aryl, heteroaryl,heterocyclic, C₃-C₁₂cycloalkyl or C₃-C₁₂cycloalkenyl. It is understoodthat the aryls, heteroaryls, alkyls, and the like can be furthersubstituted. In some cases, each substituent in a substituted moiety isadditionally optionally substituted with one or more groups, each groupbeing independently selected from C₁-C₆-alkyl, —F, —Cl, —Br, —I, —OH,—NO₂, —CN, or —NH₂.

In accordance with the invention, any of the aryls, substituted aryls,heteroaryls and substituted heteroaryls described herein, can be anyaromatic group. Aromatic groups can be substituted or unsubstituted.

It is understood that any alkyl, alkenyl, alkynyl, cycloalkyl andcycloalkenyl moiety described herein can also be an aliphatic group, analicyclic group or a heterocyclic group. An “aliphatic group” isnon-aromatic moiety that may contain any combination of carbon atoms,hydrogen atoms, halogen atoms, oxygen, nitrogen or other atoms, andoptionally contain one or more units of unsaturation, e.g., doubleand/or triple bonds. An aliphatic group may be straight chained,branched or cyclic and preferably contains between about 1 and about 24carbon atoms, more typically between about 1 and about 12 carbon atoms.In addition to aliphatic hydrocarbon groups, aliphatic groups include,for example, polyalkoxyalkyls, such as polyalkylene glycols, polyamines,and polyimines, for example. Such aliphatic groups may be furthersubstituted. It is understood that aliphatic groups may be used in placeof the alkyl, alkenyl, alkynyl, alkylene, alkenylene, and alkynylenegroups described herein.

The term “alicyclic” as used herein, denotes a monovalent group derivedfrom a monocyclic or polycyclic saturated carbocyclic ring compound bythe removal of a single hydrogen atom. Examples include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,bicyclo[2.2.1]heptyl, and bicyclo[2.2.2]octyl. Such alicyclic groups maybe further substituted.

As used herein, the term “alkoxy” employed alone or in combination withother terms means, unless otherwise stated, an alkyl group having thedesignated number of carbon atoms connected to the rest of the moleculevia an oxygen atom, such as, for example, methoxy, ethoxy, 1-propoxy,2-propoxy (isopropoxy) and the higher homologs and isomers. Preferredalkoxy are (C₁-C₃) alkoxy.

The term “aryloxy” refers to the group aryl-O— wherein the aryl group isas defined above, and includes optionally substituted aryl groups asalso defined above. The term “arylthio” refers to the group R—S—, whereR is as defined for aryl.

The terms “heterocyclic” or “heterocycloalkyl” can be usedinterchangeably and refer to a non-aromatic ring or a bi- or tri-cyclicgroup fused, bridged or spiro system, where (i) the ring system containsat least one heteroatom independently selected from oxygen, sulfur andnitrogen, (ii) the ring system can be saturated or unsaturated (iii) thenitrogen and sulfur heteroatoms may optionally be oxidized, (iv) thenitrogen heteroatom may optionally be quaternized, (v) any of the aboverings may be fused to an aromatic ring, and (vi) the remaining ringatoms are carbon atoms which may be optionally oxo-substituted oroptionally substituted with exocyclic olefinic, iminic or oximic doublebond. Representative heterocycloalkyl groups include, but are notlimited to, 1,3-dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl,imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl,isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl,quinoxalinyl, pyridazinonyl, 2-azabicyclo[2.2.1]-heptyl,8-azabicyclo[3.2.1]octyl, 5-azaspiro[2.5]octyl,1-oxa-7-azaspiro[4.4]nonanyl, 7-oxooxepan-4-yl, and tetrahydrofuryl.Such heterocyclic groups may be further substituted. Heteroaryl orheterocyclic groups can be C-attached or N-attached (where possible).

It is understood that any alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclic and cycloalkenyl moiety described herein can also be analiphatic group or an alicyclic group.

It will be apparent that in various embodiments of the invention, thesubstituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, arylalkyl, heteroarylalkyl, andheterocycloalkyl are intended to be monovalent or divalent. Thus,alkylene, alkenylene, and alkynylene, cycloaklylene, cycloalkenylene,cycloalkynylene, arylalkylene, heteroarylalkylene andheterocycloalkylene groups are to be included in the above definitions,and are applicable to provide the Formulas herein with proper valency.

The terms “halo” and “halogen,” as used herein, refer to an atomselected from fluorine, chlorine, bromine and iodine.

The term “optionally substituted”, as used herein, means that thereferenced group may be substituted or unsubstituted. In one embodiment,the referenced group is optionally substituted with zero substituents,i.e., the referenced group is unsubstituted. In another embodiment, thereferenced group is optionally substituted with one or more additionalgroup(s) individually and independently selected from groups describedherein.

The term “hydrogen” includes hydrogen and deuterium. In addition, therecitation of an atom includes other isotopes of that atom so long asthe resulting compound is pharmaceutically acceptable.

In certain embodiments, the compounds of each formula herein are definedto include isotopically labelled compounds. An “isotopically labelledcompound” is a compound in which at least one atomic position isenriched in a specific isotope of the designated element to a levelwhich is significantly greater than the natural abundance of thatisotope. For example, one or more hydrogen atom positions in a compoundcan be enriched with deuterium to a level which is significantly greaterthan the natural abundance of deuterium, for example, enrichment to alevel of at least 1%, preferably at least 20% or at least 50%. Such adeuterated compound may, for example, be metabolized more slowly thanits non-deuterated analog, and therefore exhibit a longer half-life whenadministered to a subject. Such compounds can synthesize using methodsknown in the art, for example by employing deuterated startingmaterials. Unless stated to the contrary, isotopically labelledcompounds are pharmaceutically acceptable.

The compounds described herein contain one or more asymmetric centersand thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids.The present invention is meant to include all such possible isomers, aswell as their racemic and optically pure forms. Optical isomers may beprepared from their respective optically active precursors by theprocedures described above, or by resolving the racemic mixtures. Theresolution can be carried out in the presence of a resolving agent, bychromatography or by repeated crystallization or by some combination ofthese techniques which are known to those skilled in the art. Furtherdetails regarding resolutions can be found in Jacques, et al.,Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). Whenthe compounds described herein contain olefinic double bonds, otherunsaturation, or other centers of geometric asymmetry, and unlessspecified otherwise, it is intended that the compounds include both Eand Z geometric isomers or cis- and trans-isomers. Likewise, alltautomeric forms are also intended to be included. Tautomers may be incyclic or acyclic. The configuration of any carbon-carbon double bondappearing herein is selected for convenience only and is not intended todesignate a particular configuration unless the text so states; thus, acarbon-carbon double bond or carbon-heteroatom double bond depictedarbitrarily herein as trans may be cis, trans, or a mixture of the twoin any proportion.

The term “subject” as used herein refers to a mammal. A subjecttherefore refers to, for example, dogs, cats, horses, cows, pigs, guineapigs, and the like. Preferably the subject is a human. When the subjectis a human, the subject may be referred to herein as a patient.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts of the compounds formed by the process of the presentinvention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art.

Berge, et al. describes pharmaceutically acceptable salts in detail inJ. Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be preparedin situ during the final isolation and purification of the compounds ofthe invention, or separately by reaction of the free base function witha suitable organic acid. Examples of pharmaceutically acceptable saltsinclude, but are not limited to, nontoxic acid addition salts e.g.,salts of an amino group formed with inorganic acids such as hydrochloricacid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloricacid or with organic acids such as acetic acid, maleic acid, tartaricacid, citric acid, succinic acid or malonic acid or by using othermethods used in the art such as ion exchange. Other pharmaceuticallyacceptable salts include, but are not limited to, adipate, alginate,ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate,butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Representative alkali or alkaline earth metal saltsinclude sodium, lithium, potassium, calcium, magnesium, and the like.Further pharmaceutically acceptable salts include, when appropriate,nontoxic ammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and arylsulfonate.

As used herein, the term “pharmaceutically acceptable ester” refers toesters which hydrolyze in vivo and include those that break down readilyin the human body to leave the parent compound or a salt thereof.Suitable ester groups include, for example, those derived frompharmaceutically acceptable aliphatic carboxylic acids, particularlyalkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which eachalkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.Examples of particular esters include, but are not limited to, esters ofC₁-C₆-alkanoic acids, such as acetate, propionate, butyrate and pivalateesters.

The term “hydroxy activating group,” as used herein, refers to a labilechemical moiety which is known in the art to activate a hydroxyl groupso that it will depart during synthetic procedures such as in asubstitution or an elimination reaction. Examples of hydroxyl activatinggroup include, but not limited to, mesylate, tosylate, triflate,p-nitrobenzoate, phosphonate and the like.

The term “activated hydroxyl,” as used herein, refers to a hydroxy groupactivated with a hydroxyl activating group, as defined above, includingmesylate, tosylate, triflate, p-nitrobenzoate, phosphonate groups, forexample.

The term “hydroxy protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect a hydroxyl groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the hydroxy protecting group as described hereinmay be selectively removed. Hydroxy protecting groups as known in theart are described generally in T. H. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons,New York (1999). Examples of hydroxyl protecting groups includebenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, tert-butoxy-carbonyl,isopropoxycarbonyl, diphenylmethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, acetyl, formyl,chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl,methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, allyl,benzyl, triphenyl-methyl (trityl), methoxymethyl, methylthiomethyl,benzyloxymethyl, 2-(trimethylsilyl)-ethoxymethyl, methanesulfonyl,trimethylsilyl, triisopropylsilyl, and the like.

The term “protected hydroxy,” as used herein, refers to a hydroxy groupprotected with a hydroxy protecting group, as defined above, includingbenzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups,for example.

The term “hydroxy prodrug group,” as used herein, refers to a promoietygroup which is known in the art to change the physicochemical, and hencethe biological properties of a parent drug in a transient manner bycovering or masking the hydroxy group. After said syntheticprocedure(s), the hydroxy prodrug group as described herein must becapable of reverting back to hydroxy group in vivo. Hydroxy prodruggroups as known in the art are described generally in Kenneth B. Sloan,Prodrugs, Topical and Ocular Drug Delivery, (Drugs and thePharmaceutical Sciences; Volume 53), Marcel Dekker, Inc., New York(1992) and in “Prodrugs of Alcohols and Phenols” by S. S. Dhareshwar andV. J. Stella, in Prodrugs Challenges and Rewards Part-2, (Biotechnology:Pharmaceutical Aspects), edited by V. J. Stella, et al, Springer andAAPSPress, 2007, pp 31-99.

The term “amino” as used herein, refers to the group —NH₂.

The term “substituted amino” as used herein, refers to the group —NRRwhere each R is independently selected from the group consisting ofhydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocycloalkylprovided that both R groups are not hydrogen, or a group —Y—Z, in whichY is optionally substituted alkylene and Z is alkenyl, cycloalkenyl, oralkynyl.

The term “amino protecting group” as used herein, refers to a labilechemical moiety which is known in the art to protect an amino groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the amino protecting group as described hereinmay be selectively removed. Amino protecting groups as known in the aredescribed generally in T. H. Greene and P. G. M. Wuts, Protective Groupsin Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999).Examples of amino protecting groups include, but are not limited to,t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, and thelike.

The term “leaving group” means a functional group or atom which can bedisplaced by another functional group or atom in a substitutionreaction, such as a nucleophilic substitution reaction. By way ofexample, representative leaving groups include chloro, bromo and iodogroups; sulfonic ester groups, such as mesylate, tosylate, brosylate,nosylate and the like; and acyloxy groups, such as acetoxy,trifluoroacetoxy and the like.

As used herein, the term “pharmaceutically acceptable ester” refers toesters of the compounds formed by the process of the present inventionwhich hydrolyze in vivo and include those that break down readily in thehuman body to leave the parent compound or a salt thereof. Suitableester groups include, for example, those derived from pharmaceuticallyacceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic,cycloalkanoic and alkanedioic acids, in which each alkyl or alkenylmoiety advantageously has not more than 6 carbon atoms. Examples ofparticular esters include, but are not limited to, formates, acetates,propionates, butyrates, acrylates and ethylsuccinates.

The term “pharmaceutically acceptable prodrugs” as used herein refers tothose prodrugs of the compounds formed by the process of the presentinvention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswith undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use, as well as the zwitterionic forms, where possible,of the compounds of the present invention. “Prodrug”, as used hereinmeans a compound, which is convertible in vivo by metabolic means (e.g.by hydrolysis) to afford any compound delineated by the Formulae of theinstant invention. Various forms of prodrugs are known in the art, forexample, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier(1985); Widder, et al. (ed.), Methods in Enzymology, Vol. 4, AcademicPress (1985); Krogsgaard-Larsen, et al., (ed). “Design and Applicationof Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191(1991); Bundgaard, et al., Journal of Drug Deliver Reviews,8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq.(1988); Higuchi and Stella (eds.) Prodrugs as Novel Drug DeliverySystems, American Chemical Society (1975); and Bernard Testa & JoachimMayer, “Hydrolysis In Drug And Prodrug Metabolism: Chemistry,Biochemistry And Enzymology,” John Wiley and Sons, Ltd. (2002).

The term “treating”, as used herein, means relieving, lessening,reducing, eliminating, modulating, or ameliorating, i.e. causingregression of the disease state or condition. Treating can also includeinhibiting, i.e. arresting the development, of an existing disease stateor condition, and relieving or ameliorating, i.e. causing regression ofan existing disease state or condition, for example when the diseasestate or condition may already be present.

The term “preventing”, as used herein means, to completely or almostcompletely stop a disease state or condition, from occurring in apatient or subject, especially when the patient or subject ispredisposed to such or at risk of contracting a disease state orcondition.

Additionally, the compounds of the present invention, for example, thesalts of the compounds, can exist in either hydrated or unhydrated (theanhydrous) form or as solvates with other solvent molecules. Nonlimitingexamples of hydrates include monohydrates, dihydrates, etc. Nonlimitingexamples of solvates include ethanol solvates, acetone solvates, etc.

“Solvates” means solvent addition forms that contain eitherstoichiometric or non-stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. If the solvent is waterthe solvate formed is a hydrate, when the solvent is alcohol, thesolvate formed is an alcoholate. Hydrates are formed by the combinationof one or more molecules of water with one of the substances in whichthe water retains its molecular state as H₂O, such combination beingable to form one or more hydrate.

As used herein, the term “analog” refers to a chemical compound that isstructurally similar to another but differs slightly in composition (asin the replacement of one atom by an atom of a different element or inthe presence of a particular functional group, or the replacement of onefunctional group by another functional group). Thus, an analog is acompound that is similar to or comparable in function and appearance tothe reference compound.

The term “aprotic solvent,” as used herein, refers to a solvent that isrelatively inert to proton activity, i.e., not acting as a proton-donor.Examples include, but are not limited to, hydrocarbons, such as hexaneand toluene, for example, halogenated hydrocarbons, such as, forexample, methylene chloride, ethylene chloride, chloroform, and thelike, heterocyclic compounds, such as, for example, tetrahydrofuran andN-methylpyrrolidinone, and ethers such as diethyl ether,bis-methoxymethyl ether. Such solvents are well known to those skilledin the art, and individual solvents or mixtures thereof may be preferredfor specific compounds and reaction conditions, depending upon suchfactors as the solubility of reagents, reactivity of reagents andpreferred temperature ranges, for example. Further discussions ofaprotic solvents may be found in organic chemistry textbooks or inspecialized monographs, for example: Organic Solvents PhysicalProperties and Methods of Purification, 4th ed., edited by John A.Riddick et al., Vol. II, in the Techniques of Chemistry Series, JohnWiley & Sons, N Y, 1986.

The terms “protogenic organic solvent” or “protic solvent” as usedherein, refer to a solvent that tends to provide protons, such as analcohol, for example, methanol, ethanol, propanol, isopropanol, butanol,t-butanol, and the like. Such solvents are well known to those skilledin the art, and individual solvents or mixtures thereof may be preferredfor specific compounds and reaction conditions, depending upon suchfactors as the solubility of reagents, reactivity of reagents andpreferred temperature ranges, for example. Further discussions ofprotogenic solvents may be found in organic chemistry textbooks or inspecialized monographs, for example: Organic Solvents PhysicalProperties and Methods of Purification, 4th ed., edited by John A.Riddick et al., Vol. II, in the Techniques of Chemistry Series, JohnWiley & Sons, N Y, 1986.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm “stable”, as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., therapeutic or prophylacticadministration to a subject).

The synthesized compounds can be separated from a reaction mixture andfurther purified by a method such as column chromatography, highpressure liquid chromatography, or recrystallization. Additionally, thevarious synthetic steps may be performed in an alternate sequence ororder to give the desired compounds. In addition, the solvents,temperatures, reaction durations, etc. delineated herein are forpurposes of illustration only and variation of the reaction conditionscan produce the desired isoxazole products of the present invention.Synthetic chemistry transformations and protecting group methodologies(protection and deprotection) useful in synthesizing the compoundsdescribed herein include, for example, those described in R. Larock,Comprehensive Organic Transformations, VCH Publishers (1989); T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d.Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser andFieser's Reagents for Or anic Synthesis, John Wiley and Sons (1994); andL. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, JohnWiley and Sons (1995).

The compounds of this invention may be modified by appending variousfunctionalities via synthetic means delineated herein to enhanceselective biological properties. Such modifications include those whichincrease biological penetration into a given biological system (e.g.,blood, lymphatic system, central nervous system), increase oralavailability, increase solubility to allow administration by injection,alter metabolism and alter rate of excretion.

Pharmaceutical Compositions

The pharmaceutical compositions of the present invention comprise atherapeutically effective amount of a compound of the present inventionFormulated together with one or more pharmaceutically acceptablecarriers. As used herein, the term “pharmaceutically acceptable carrier”means a non-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or Formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as lactose, glucose and sucrose; starches suchas corn starch and potato starch; cellulose and its derivatives such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients such as cocoabutter and suppository waxes; oils such as peanut oil, cottonseed oil;safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols;such a propylene glycol; esters such as ethyl oleate and ethyl laurate;agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the Formulator. The pharmaceuticalcompositions of this invention can be administered to humans and otheranimals orally, rectally, parenterally, intracisternally,intravaginally, intraperitoneally, topically (as by powders, ointments,or drops), buccally, or as an oral or nasal spray.

The pharmaceutical compositions of this invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir, preferably by oraladministration or administration by injection. The pharmaceuticalcompositions of this invention may contain any conventional non-toxicpharmaceutically-acceptable carriers, adjuvants or vehicles. In somecases, the pH of the Formulation may be adjusted with pharmaceuticallyacceptable acids, bases or buffers to enhance the stability of theFormulated compound or its delivery form. The term parenteral as usedherein includes subcutaneous, intracutaneous, intravenous,intramuscular, intraarticular, intraarterial, intrasynovial,intrasternal, intrathecal, intralesional and intracranial injection orinfusion techniques.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose, any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable Formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle. Injectable depot forms are made by forming microencapsulematrices of the drug in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of drug to polymerand the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableFormulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or: a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragées, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical Formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositionswhich can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic Formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

Unless otherwise defined, all technical and scientific terms used hereinare accorded the meaning commonly known to one with ordinary skill inthe art. All publications, patents, published patent applications, andother references mentioned herein are hereby incorporated by referencein their entirety.

ABBREVIATIONS

Abbreviations which have been used in the descriptions of the schemesand the examples that follow are:

-   -   AcOH for acetic acid;    -   AIBN for azobisisobutyronitrile;    -   ASK1 for apoptosis signal-regulating kinase 1;    -   ATP for adenosine triphosphate;    -   Boc for tert-butyloxycarbonyl;    -   Boc₂O for di-tert-butyl dicarbonate;    -   BOP-Cl for bis(2-oxo-3-oxazolidinyl)phosphinic chloride;    -   Cbz for benzyloxycarbonyl;    -   Cbz-Cl for benzyl chloroformate;    -   CDI for carbonyldiimidazole;    -   DCC for N,N′-dicyclohexylcarbodiimide;    -   1,2-DCE for 1,2-dichloroethane;    -   DCM for dichloromethane;    -   DIPEA or Hunig's base or i-Pr₂NEt for N,N-diisopropylethylamine;    -   DMA for N,N-dimethylacetamide;    -   DMAP for N,N-dimethylaminopyridine;    -   DMF for N,N-dimethyl formamide;    -   dppp for 1,3-bis(diphenylphosphino)propane;    -   EDC for 1-(3-diethylaminopropyl)-3-ethylcarbodiimide        hydrochloride;    -   EGTA for ethylene        glycol-bis(2-aminoethylether)-N,N,N′,N′-tetraacetic acid;    -   ESI for electrospray ionization;    -   Et₃N or TEA for triethylamine;    -   EtOAc for ethyl acetate;    -   Ghosez's Reagent for 1-chloro-N,N,2-trimethyl-1-propenylamine;    -   h, hr, or hrs for hours;    -   HATU for        1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium        3-oxid hexafluorophosphate;    -   HEPES for 4-(2-Hydroxyethyl)piperazine-1-ethanesulfonic acid,        N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid);    -   IC₅₀ for half maximal inhibitory concentration;    -   KOt-Bu for potassium tert-butoxide;    -   LC-MS for liquid chromatography-mass spectrometry;    -   MeCN or ACN for acetonitrile;    -   min or mins for minutes;    -   MTBE or TBME for methyl tert-butyl ether;    -   m/z for mass-to-charge ratio;    -   NaOt-Bu for sodium tert-butoxide;    -   NMP for 1-methyl-2-pyrrolidinone;    -   NMR for nuclear magnetic resonance spectroscopy;    -   Pd/C for palladium on carbon;    -   PhMe or tol for toluene;    -   OTBS for tert-butyldimethylsiloxy;    -   OTf or triflate for trifluoromethanesulfonate;    -   PyAOP for 7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium        hexafluorophosphate;    -   PyBOP for benzotriazol-1-yl-oxytripyrrolidinophosphonium        hexafluorophosphate;    -   rt for room temperature;    -   STK3 for serine/threonine-protein kinase 3;    -   Tf₂O for trifluoromethanesulfonic anhydride;    -   TFA for trifluoroacetic acid;    -   THF for tetrahydrofuran;    -   TR-FRET for time-resolved fluorescence energy transfer.        Synthetic Methods

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic schemes thatillustrate the methods by which the compounds of the invention may beprepared, which are intended as an illustration only and not to limitthe scope of the invention. Various changes and modifications to thedisclosed embodiments will be apparent to those skilled in the art andsuch changes and modifications including, without limitation, thoserelating to the chemical structures, substituents, derivatives, and/ormethods of the invention may be made without departing from the spiritof the invention and the scope of the appended claims.

As shown in Scheme 1, compounds of Formula (Ie) are prepared from thecompound of Formula (1-1) wherein X³ and n are as previously defined. X⁴is Br, Cl, I, or OTf. Thus, the compound of Formula (1-1) is reactedwith a suitable N-functionalizing reagent to afford a compound ofFormula (1-2), wherein R¹⁵ is a suitable nitrogen protecting group, suchas, but not limited to Boc or Cbz. If R¹⁵ is Cbz, a compound of Formula(1-1) is reacted with Cbz-Cl to afford a compound of Formula (1-2) usinga suitable base such as, but not limited to, Et₃N, DIPEA, DMAP, orpyridine. The reaction solvent can be, but is not limited to, THF orDCM. The reaction temperature is from −20° C. to 40° C. If R¹⁵ is Boc, acompound of Formula (1-1) is reacted with Boc₂O to afford a compound ofFormula (1-2) using a suitable base such as, but not limited to, Et₃N,DIPEA, DMAP, or pyridine. The reaction solvent can be, but is notlimited to, THF or DCM. The reaction temperature is from −20° C. to 40°C. The compound of Formula (1-2) is converted to a compound of Formula(1-3), wherein R¹⁴ is an alkyl group, such as, but not limited to,methyl, ethyl, propyl, tert-butyl, and isopropyl. Thus, the compound ofFormula (1-2) is reacted with a suitable metallating reagent, such as,but not limited to, isopropylmagnesium chloride, followed by reactingthe resultant intermediate with carbon dioxide to afford a compound ofFormula (1-3). The reaction solvent can be, but is not limited to, THF.The reaction temperature is from −80° C. to 25° C. Alternatively, thecompound of Formula (1-2) is reacted with a suitable palladium catalyst,a suitable ligand, a suitable base, a suitable alcohol, and carbonmonoxide to afford a compound of Formula (1-3). The palladium catalystcan be, but is not limited to, palladium(II) acetate,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), ortetrakis(triphenylphosphine) palladium(0). The ligand, can be, but isnot limited to, 1,3-bis(diphenylphosphino)propane, or1,4-bis(diphenylphosphino)butane. The base can be, but is not limitedto, Et₃N, DIPEA, K₂CO₃, Na₂CO₃, or Cs₂CO₃. The alcohol can be, but isnot limited to, methanol, ethanol, 2-propanol, n-propanol, ortert-butanol. The reaction solvent can be, but is not limited to, DMF,NMP, or DMA. The reaction temperature is from 25° C. to 150° C. Thecompound of Formula (1-3) is hydrolyzed to afford a compound of Formula(1-4) using a suitable hydroxide source such as, but not limited to,NaOH or LiOH. Alternatively, if R¹⁴ is tert-butyl, then the compound ofFormula (1-3) is reacted with a suitable acid to afford a compound ofFormula (1-4). The acid can be, but is not limited to, hydrochloric acidor TFA. The compound of Formula (1-4) is reacted with a suitablechlorinating reagent such as, but not limited to, oxalyl chloride incombination with a catalytic quantity of DMF, thionyl chloride, orGhosez's reagent to afford a compound of Formula (1-5). The reactionsolvent can be, but is not limited to, THF or DCM. The reactiontemperature is from −20° C. to 40° C. The compound of Formula (1-5) isreacted with a compound of Formula (1-6), wherein X¹, X², R¹ and R² areas previously defined, to afford a compound of Formula (1-6) using asuitable base such as, but not limited to, Et₃N, DMAP, pyridine, orDIPEA. The reaction solvent can be, but is not limited to, THF, DCM,pyridine and toluene. The reaction temperature is from −20° C. to 40° C.Alternatively, the compound of Formula (1-4) is reacted with a compoundof Formula (1-6) to afford a compound of Formula (1-7) using a suitablecoupling reagent such as, but not limited to, BOP-Cl, CDI, DCC, EDC,HATU, PyAOP or PyBOP in the presence of a suitable base such as, but notlimited to, Et₃N or DIPEA. The reaction solvent can be, but is notlimited to, THF, DCM and DMF. The reaction temperature is from −20° C.to 40° C. Alternatively, the compound of Formula (1-3) is reacted with acompound of Formula (1-6) in the presence of trimethylaluminum to afforda compound of Formula (1-7). The reaction solvent can be, but is notlimited to, DCM or PhMe. The reaction temperature is from 0° C. to 100°C. Alternatively, the compound of Formula (1-2) can be reacted with acompound of Formula (1-6) and carbon monoxide in the presence of asuitable palladium catalyst, a suitable ligand and a suitable base toafford a compound of Formula (1-7). The palladium catalyst can be, butis not limited to, palladium(II) acetate,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), ortetrakis(triphenylphosphine) palladium(0). The ligand, can be, but isnot limited to, 1,3-bis(diphenylphosphino)propane, or1,4-bis(diphenylphosphino)butane. The base can be, but is not limitedto, Et₃N, DIPEA, K₂CO₃, Na₂CO₃, or Cs₂CO₃. The reaction solvent can be,but is not limited to, DMF, NMP, or DMA. The reaction temperature isfrom 25° C. to 150° C. If R¹⁵ is Cbz, the compound of Formula (1-7) isreacted with palladium on carbon in the presence of hydrogen gas toafford a compound of Formula (1-8). The reaction solvent can be, but isnot limited to, MeOH, EtOH, EtOAc, and THF. If R¹⁵ is Boc, the compoundof Formula (1-7) is reacted with a suitable acid, such as, but notlimited to, hydrochloric acid or TFA to afford a compound of Formula(1-8). The reaction solvent can be, but is not limited to, MeOH, EtOH,EtOAc, THF, and 1,4-dioxane. Compounds of Formula (1-8) are reacted witha suitable combination of reagents to afford compounds of Formula (Ie).The reagent combinations may be, but are not limited to:

-   -   1) An aldehyde in combination with a suitable reducing agent,        such as, but not limited to, NaBH₄, NaBH(OAc)₃, or NaBH₃CN. The        reaction solvent can be, but is not limited to, DCM, 1,2-DCE, or        THF.    -   2) A ketone in combination with a suitable reducing agent, such        as, but not limited to, NaBH₄, NaBH(OAc)₃, or NaBH₃CN. The        reaction solvent can be, but is not limited to, DCM, 1,2-DCE, or        THF.    -   3) An alkyl halide, alkyl mesylate, or alkyl tosylate in        combination with a suitable base such as, but not limited to,        NaH, NaOt-Bu, KOt-Bu, Et₃N, or DIPEA. The reaction solvent can        be, but is not limited to, DCM or THF.    -   4) An aryl-, heteroaryl-, or alkenyl-halide, or an aryl- or        heteroaryl-, or alkenyl-triflate in combination with a suitable        base, palladium(0) catalyst, ligand, and solvent. The base can        be, but is not limited to, NaOt-Bu or KOt-Bu. The palladium(0)        catalyst can be, but is not limited to, Pd(PPh₃)₄ or Pd₂(dba)₃.        The ligand can be, but is not limited to, P(o-tolyl)₃ or        (2-biphenyl)di-tert-butylphosphine. The solvent can be, but is        not limited to, toluene or THF.    -   5) An acyl chloride in the presence of a suitable base such as,        but not limited to, Et₃N, DIPEA, or DMAP. The reaction solvent        can be, but is not limited to, DCM or THF.    -   6) A chloroformate in the presence of a suitable base such as,        but not limited to, Et₃N, DIPEA, or DMAP. The reaction solvent        can be, but is not limited to, DCM or THF.    -   7) A sulfonyl chloride in the presence of a suitable base such        as, but not limited to, Et₃N, DIPEA, or DMAP. The reaction        solvent can be, but is not limited to, DCM or THF.    -   8) An isocyanate in the presence of a suitable base such as, but        not limited to, Et₃N, DIPEA, or DMAP. The reaction solvent can        be, but is not limited to, DCM or THF.    -   9) A primary or secondary amine in the presence of a suitable        activating reagent such as, but not limited to, phosgene,        triphosgene, or CDI. The reaction solvent can be, but is not        limited to, DCM or THF.    -   10) A carboxylic acid in the presence of a suitable coupling        reagent, and base. The coupling reagent can be, but is not        limited to, BOP-Cl, CDI, DCC, EDC, HATU, PyAOP or PyBOP. The        base can be, but is not limited to, Et₃N, DIPEA, or pyridine.    -   11) An aryl or heteroaryl halide in the presence of a suitable        base, such as, but not limited to, Cs₂CO₃, K₂CO₃, Et₃N, DBU,        DIPEA, or pyridine. The reaction solvent can be, but is not        limited to, DCM, THF, DMF, or NMP.

As shown in Scheme 2, compounds of Formula (Ie) are prepared from thecompound of Formula (1-1) wherein X³ and n are as previously defined. X⁴is Br, Cl, I, or OTf. Thus, the compound of Formula (1-1) is reactedwith a suitable N-functionalizing reagent to afford a compound ofFormula (1-2), wherein R¹⁵ is a suitable nitrogen protecting group, suchas, but not limited to Boc or Cbz. If R¹⁵ is Cbz, a compound of Formula(1-1) is reacted with Cbz-Cl to afford a compound of Formula (1-2) usinga suitable base such as, but not limited to, Et₃N, DIPEA, DMAP, orpyridine. The reaction solvent can be, but is not limited to, THF orDCM. The reaction temperature is from −20° C. to 40° C. If R¹⁵ is Boc, acompound of Formula (1-1) is reacted with Boc₂O to afford a compound ofFormula (1-2) using a suitable base such as, but not limited to, Et₃N,DIPEA, DMAP, or pyridine. The reaction solvent can be, but is notlimited to, THF or DCM. The reaction temperature is from −20° C. to 40°C. The compound of Formula (1-2) is converted to a compound of Formula(2-1), wherein R¹⁶, R¹⁷, and R¹⁸ are hydrogen, substituted orunsubstituted —C₁-C₈ alkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstituted—C₃-C₈ cycloalkyl, substituted or unsubstituted arylalkyl, substitutedor unsubstituted 3- to 8-membered heterocycloalkyl, substituted orunsubstituted heteroarylalkyl, or R¹⁶ and R¹⁷ are taken together to forman optionally substituted cycloalkyl or heterocycloalkyl, or R¹⁷ and R¹⁸are taken together to form an optionally substituted cycloalkyl orheterocycloalkyl. Thus, the compound of Formula (1-2) is reacted with asuitable boronic ester or boronic acid in the presence of a suitablepalladium catalyst, a suitable ligand, and a suitable base to afford acompound of Formula (2-1). The boronic ester or boronic acid can be, butis not limited to, vinylboronic acid pinacol ester ortrans-2-(phenyl)vinylboronic acid pinacol ester. The palladium catalystcan be, but is not limited to, palladium(II) acetate,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), ortetrakis(triphenylphosphine) palladium(0). The ligand, can be, but isnot limited to, 1,3-bis(diphenylphosphino)propane, PCy₃HBF₄, PCy₃, orPPh₃. The base can be, but is not limited to, Et₃N, DIPEA, K₂CO₃,Na₂CO₃, Cs₂CO₃, or K₃PO₄. The reaction solvent can be, but is notlimited to, DMF, NMP, DMA, H₂O, or 1,4-dioxane. The reaction temperatureis from 25° C. to 150° C. Alternatively, the compound of Formula (1-2)is reacted with a suitable organotin reagent in the presence of asuitable palladium catalyst and a suitable ligand to afford a compoundof Formula (2-1). The organotin reagent can be, but is not limited to,tributyl(vinyl)tin. The palladium catalyst can be, but is not limitedto, tetrakis(triphenylphosphine) palladium(0), palladium(II) acetate, ortris(dibenzylideneacetone)dipalladium(0). The ligand can be, but is notlimited to, triphenylphosphine, tri-tert-butylphosphine,tri(ortho-tolyl)phosphine, or2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl. The reactionsolvent can be, but is not limited to, THF, 1,4-dioxane, or toluene. Thereaction temperature is from 25° C. to 150° C. The compound of Formula(2-1) is reacted with a suitable oxidant in the presence of a suitablebase to afford a compound of Formula (2-2). The oxidant can be, but isnot limited to osmium tetroxide, or a combination of osmium tetroxideand sodium periodate. The base can be, but is not limited to,2,6-lutidine. The reaction solvent can be, but is not limited to,1,4-dioxane, H₂O or a combination of these. The reaction temperature isfrom 0° C. to 50° C. Alternatively, the compound of Formula (2-1) isreacted with ozone followed by a suitable reducing agent to afford acompound of Formula (2-2). The reducing agent can be, but is not limitedto, dimethylsulfide or triphenylphosphine. The reaction solvent can be,but is not limited to, methanol or dichloromethane. The reactiontemperature is from −80° C. to 25° C. The compound of Formula (2-2) isreacted with a suitable chlorous acid source in the presence of asuitable hypochlorous acid scavenger and a suitable buffer to afford acompound of Formula (1-4). The chlorous acid source can be, but is notlimited to, NaClO₂. The hypochlorous acid scavenger can be, but is notlimited to, 2-methyl-2-butene. The buffer can be, but is not limited to,NaH₂PO₄. The reaction solvent can be, but is not limited to, THF,tert-butanol, CH₃CN, H₂O, or a combination of these. The reactiontemperature is from 0° C. to 50° C. Alternatively, the compound ofFormula (2-1) is reacted with a catalytic quantity of RuCl₃ in thepresence of a suitable oxidant to afford a compound of Formula (1-4).The oxidant can be, but is not limited to sodium periodate. The reactionsolvent can be, but is not limited to, EtOAc, CCl₄, CH₂Cl₂, CH₃CN, H₂O,or a combination of these. The reaction temperature is from 0° C. to 50°C. The compound of Formula (1-4) is reacted with a suitable chlorinatingreagent such as, but not limited to, oxalyl chloride in combination witha catalytic quantity of DMF, thionyl chloride, or Ghosez's reagent toafford a compound of Formula (1-5). The reaction solvent can be, but isnot limited to, THF or DCM. The reaction temperature is from −20° C. to40° C. The compound of Formula (1-5) is reacted with a compound ofFormula (1-6), wherein X¹, X², R¹ and R² are as previously defined, toafford a compound of Formula (1-6) using a suitable base such as, butnot limited to, Et₃N, DMAP, pyridine, or DIPEA. The reaction solvent canbe, but is not limited to, THF, DCM, pyridine and toluene. The reactiontemperature is from −20° C. to 40° C. Alternatively, the compound ofFormula (1-4) is reacted with a compound of Formula (1-6) to afford acompound of Formula (1-7) using a suitable coupling reagent such as, butnot limited to, BOP-Cl, CDI, DCC, EDC, HATU, PyAOP or PyBOP in thepresence of a suitable base such as, but not limited to, Et₃N or DIPEA.The reaction solvent can be, but is not limited to, THF, DCM and DMF.The reaction temperature is from −20° C. to 40° C. Alternatively, thecompound of Formula (1-3) is reacted with a compound of Formula (1-6) inthe presence of trimethylaluminum to afford a compound of Formula (1-7).The reaction solvent can be, but is not limited to, DCM or PhMe. Thereaction temperature is from 0° C. to 100° C. Alternatively, thecompound of Formula (1-2) can be reacted with a compound of Formula(1-6) and carbon monoxide in the presence of a suitable palladiumcatalyst, a suitable ligand and a suitable base to afford a compound ofFormula (1-7). The palladium catalyst can be, but is not limited to,palladium(II) acetate,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), ortetrakis(triphenylphosphine) palladium(0). The ligand, can be, but isnot limited to, 1,3-bis(diphenylphosphino)propane, or1,4-bis(diphenylphosphino)butane. The base can be, but is not limitedto, Et₃N, DIPEA, K₂CO₃, Na₂CO₃, or Cs₂CO₃. The reaction solvent can be,but is not limited to, DMF, NMP, or DMA. The reaction temperature isfrom 25° C. to 150° C. If R¹⁵ is Cbz, the compound of Formula (1-7) isreacted with palladium on carbon in the presence of hydrogen gas toafford a compound of Formula (1-8). The reaction solvent can be, but isnot limited to, MeOH, EtOH, EtOAc, and THF. If R¹⁵ is Boc, the compoundof Formula (1-7) is reacted with a suitable acid, such as, but notlimited to, hydrochloric acid or TFA to afford a compound of Formula(1-8). The reaction solvent can be, but is not limited to, MeOH, EtOH,EtOAc, THF, and 1,4-dioxane. Compounds of Formula (1-8) are reacted witha suitable combination of reagents to afford compounds of Formula (Ie).The reagent combinations may be, but are not limited to:

-   -   1) An aldehyde in combination with a suitable reducing agent,        such as, but not limited to, NaBH₄, NaBH(OAc)₃, or NaBH₃CN. The        reaction solvent can be, but is not limited to, DCM, 1,2-DCE, or        THF.    -   2) A ketone in combination with a suitable reducing agent, such        as, but not limited to, NaBH₄, NaBH(OAc)₃, or NaBH₃CN. The        reaction solvent can be, but is not limited to, DCM, 1,2-DCE, or        THF.    -   3) An alkyl halide, alkyl mesylate, or alkyl tosylate in        combination with a suitable base such as, but not limited to,        NaH, NaOt-Bu, KOt-Bu, Et₃N, or DIPEA. The reaction solvent can        be, but is not limited to, DCM or THF.    -   4) An aryl-, heteroaryl-, or alkenyl-halide, or an aryl- or        heteroaryl-, or alkenyl-triflate in combination with a suitable        base, palladium(0) catalyst, ligand, and solvent. The base can        be, but is not limited to, NaOt-Bu or KOt-Bu. The palladium(0)        catalyst can be, but is not limited to, Pd(PPh₃)₄ or Pd₂(dba)₃.        The ligand can be, but is not limited to, P(o-tolyl)₃ or        (2-biphenyl)di-tert-butylphosphine. The solvent can be, but is        not limited to, toluene or THF.    -   5) An acyl chloride in the presence of a suitable base such as,        but not limited to, Et₃N, DIPEA, or DMAP. The reaction solvent        can be, but is not limited to, DCM or THF.    -   6) A chloroformate in the presence of a suitable base such as,        but not limited to, Et₃N, DIPEA, or DMAP. The reaction solvent        can be, but is not limited to, DCM or THF.    -   7) A sulfonyl chloride in the presence of a suitable base such        as, but not limited to, Et₃N, DIPEA, or DMAP. The reaction        solvent can be, but is not limited to, DCM or THF.    -   8) An isocyanate in the presence of a suitable base such as, but        not limited to, Et₃N, DIPEA, or DMAP. The reaction solvent can        be, but is not limited to, DCM or THF.    -   9) A primary or secondary amine in the presence of a suitable        activating reagent such as, but not limited to, phosgene,        triphosgene, or CDI. The reaction solvent can be, but is not        limited to, DCM or THF.    -   10) A carboxylic acid in the presence of a suitable coupling        reagent, and base. The coupling reagent can be, but is not        limited to, BOP-Cl, CDI, DCC, EDC, HATU, PyAOP or PyBOP. The        base can be, but is not limited to, Et₃N, DIPEA, or pyridine.    -   11) An aryl or heteroaryl halide in the presence of a suitable        base, such as, but not limited to, Cs₂CO₃, K₂CO₃, Et₃N, DBU,        DIPEA, or pyridine. The reaction solvent can be, but is not        limited to, DCM, THF, DMF, or NMP.

EXAMPLES

The compounds and processes of the present invention will be betterunderstood in connection with the following examples, which are intendedas an illustration only and not limiting of the scope of the invention.Various changes and modifications to the disclosed embodiments will beapparent to those skilled in the art and such changes and modificationsincluding, without limitation, those relating to the chemicalstructures, substituents, derivatives, Formulations and/or methods ofthe invention may be made without departing from the spirit of theinvention and the scope of the appended claims.

Example 1: Synthesis ofN-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-pivaloyl-5,6,7,8-tetrahydro-2,6-naphthyridine-3-carboxamide

Step 1. Synthesis of ethyl7-((6-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)carbamoyl)-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate

A mixture of tert-butyl7-chloro-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate (3.0 g, 11.16mmol), Pd(OAc)₂ (0.251 g, 1.12 mmol), 1,3-bis(diphenylphosphino)propane(0.921 g, 2.23 mmol), and Et₃N (4.67 ml, 33.5 mmol) in DMF (29.8ml)/EtOH (14.9 ml) were stirred under a balloon of CO at 80° C.overnight. The reaction was quenched with H₂O/brine and diluted withEtOAc. The layers were separated and the organic layer was washed withH₂O/brine (2×). The organic layer was dried (MgSO₄), filtered, andconcentrated under reduced pressure. The resultant brown gum waspurified by column chromatography eluting with hexanes/EtOAc (0%EtOAc→75% EtOAc) to afford 2-(tert-butyl) 7-ethyl3,4-dihydro-2,6-naphthyridine-2,7(1H)-dicarboxylate (2.17 g, 7.08 mmol,64% yield) as a pale yellow oil: ¹H NMR (400 MHz, Chloroform-d) δ 8.52(s, 1H), 7.89 (s, 1H), 4.64 (s, 2H), 4.47 (q, J=7.1 Hz, 2H), 3.70 (t,J=5.8 Hz, 2H), 2.90 (t, J=5.8 Hz, 2H), 1.50 (s, 9H), 1.44 (t, J=7.1 Hz,3H).

Step 2. Synthesis of ethyl5,6,7,8-tetrahydro-2,6-naphthyridine-3-carboxylate

A solution of 2-(tert-butyl) 7-ethyl3,4-dihydro-2,6-naphthyridine-2,7(1H)-dicarboxylate (200 mg, 0.7 mmol)in TFA (1.0 mL) and DCM (5.0 mL) was stirred for 1 h at rt. Theresulting mixture was concentrated under reduced pressure, and the crudeproduct was used in the next step directly without further purification.

Step 3. Synthesis of diethyl3,4-dihydro-2,6-naphthyridine-2,7(1H)-dicarboxylate

Ethyl chloroformate (0.16 mL, 178 mg, 1.6 mmol) was added to a solutionof ethyl 5,6,7,8-tetrahydro-2,6-naphthyridine-3-carboxylate (135 mg, 0.7mmol) and Et₃N (0.46 mL, 331 mg, 3.3 mmol) in DCM (5.0 mL) at 0° C. Thecold bath was removed and the reaction was stirred for 1 h at rt. Thereaction was concentrated under reduced pressure. The resultant residuewas purified by reverse phase flash chromatography eluting with MeCN/H₂O(5% MeCN→93% MeCN over 25 minutes) to afford3,4-dihydro-2,6-naphthyridine-2,7(1H)-dicarboxylate (150 mg, 0.54 mmol,82%) as a pale yellow oil.

Step 4. Synthesis of6-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amine

A mixture of 6-aminopyridine-2-carbohydrazide (2.4 g, 15.4 mmol),2-methoxy-4,5-dihydro-3H-pyrrole (1.7 g, 17.1 mmol) and AcOH (2.0 mL,34.9 mmol) in 2-pentanol (20.0 mL) was heated at reflux overnight. Aftercooling to rt, the mixture was basified with saturated NaHCO₃ andextracted with CH₂Cl₂ (3×30 mL). The combined organic layers were dried(Na₂SO₄), filtered, and concentrated under reduced pressure. Theresultant white solid was washed with a acetonitrile and hexanessuccessively to give6-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amine (2.4g, 11.4 mmol, 77%) as a white solid: LC-MS, ES⁺: m/z 202.05 [M+H]⁺; ¹HNMR (500 MHz, Chloroform-d) δ 7.65 (dd, J=7.4, 1.1 Hz, 1H), 7.55 (t,J=7.8 Hz, 1H), 6.54 (d, J=8.1 Hz, 1H), 4.42 (t, J=7.2 Hz, 2H), 3.01 (t,J=7.7 Hz, 2H), 2.78 (m, 2H).

Step 5. Synthesis of ethyl7-((6-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)carbamoyl)-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate

Representative Procedure for Amide Formation with Trimethylaluminum.

6-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amine (40mg, 0.2 mmol) was added to a solution of trimethylaluminum (0.35 mL, 0.7mmol of a 2.0M solution in PhMe) in CH₂Cl₂ (5.0 mL) at 0° C. The coldbath was removed and the reaction was stirred for 1 h at rt.3,4-dihydro-2,6-naphthyridine-2,7(1H)-dicarboxylate (50 mg, 0.2 mmol)was added and the reaction was heated at 35° C. overnight. The reactionwas cooled to rt and quenched with H₂O and diluted with CH₂Cl₂. Thelayers were separated and the aqueous layer was extracted with CH₂Cl₂(2×). The combined organic layers were washed with brine, dried(Na₂SO₄), filtered, and concentrated under reduced pressure. Theresultant yellow gum was purified by reverse phase flash chromatographyeluting with MeCN/H₂O (0% MeCN→45% MeCN) to afford ethyl7-((6-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)carbamoyl)-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate(16.8 mg, 0.04 mmol, 20% yield) as an off-white solid.

Example 2: Synthesis of ethyl7-((6-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate

Step 1. Synthesis of6-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)pyridin-2-amine

A mixture of 6-aminopyridine-2-carbohydrazide (4.0 g, 26.3 mmol),6-methoxy-2,3,4,5-tetrahydropyridine (3.6 g, 31.6 mmol) and AcOH (3.5mL, 61.1 mmol) in 2-pentanol (35.0 mL) was heated at reflux overnight.After cooling to rt, the mixture was basified with saturated NaHCO₃ andextracted with CH₂Cl₂ (3×30 mL). The combined organic layers were dried(Na₂SO₄), filtered, and concentrated under reduced pressure. Theresultant white solid was washed with a acetonitrile and hexanessuccessively to give6-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)pyridin-2-amine(4.4 g, 20.4 mmol, 77%) as a white solid: LC-MS, ES⁺: m/z 216.20 [M+H]⁺;¹H NMR (500 MHz, Chloroform-d) δ 7.65-7.52 (m, 2H), 6.56 (d, J=8.0 Hz,1H), 4.49 (t, J=6.0 Hz, 2H), 3.07 (t, J=6.4 Hz, 2H), 2.07-1.90 (m, 4H).

Example 2 was prepared from6-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)pyridin-2-amineand 3,4-dihydro-2,6-naphthyridine-2,7(1H)-dicarboxylate according to therepresentative procedure for amide formation with trimethylaluminum.

Example 3: Synthesis of ethyl(R)-7-((6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)carbamoyl)-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate

Step 1. Synthesis of (R)-5-methylpyrrolidin-2-one

To a solution of (S)-5-(bromomethyl)pyrrolidin-2-one (5.0 g, 28.1 mmol)in toluene (100 mL) was added Bu₃SnH (9.1 mL, 33.7 mmol) and AIBN (1.4mL, 0.28 mmol) (0.2M in toluene) and the reaction was heated at 80° C.for 5 h. The reaction was cooled to rt and was concentrated underreduced pressure. The resultant pale yellow oil was purified by columnchromatography eluting with CH₂Cl₂/MeOH (0% MeOH→8% MeOH) to give(R)-5-methylpyrrolidin-2-one (2.6 g, 26.2 mmol, 93% yield) as acolorless oil: ¹H NMR (400 MHz, Chloroform-d) δ 5.93 (br s, 1H), 3.78(h, J=6.4 Hz, 1H), 2.43-2.21 (comp, 3H), 1.73-1.60 (m, 1H), 1.22 (d,J=6.3 Hz, 3H).

Step 2. Synthesis of (R)-5-methoxy-2-methyl-3,4-dihydro-2H-pyrrole

Trimethyloxonium tetrafluoroborate (1.3 g, 9.1 mmol) was added portionwise to a solution of (R)-5-methylpyrrolidin-2-one (600 mg, 6.1 mmol) inCH₂Cl₂ (8.0 mL) at 0° C. over 5 min. The reaction was stirred overnightat rt. The reaction was quenched with sat. NaHCO₃ and diluted withCH₂Cl₂. The layers were separated and the aqueous layer was extractedwith CH₂Cl₂ (2×30 mL). The combined organic layers were dried (Na₂SO₄)and filtered. AcOH (2.0 mL) was added to the filtrate, and the mixturewas concentrated under reduced pressure. The crude product (600 mg) wastaken on to the next step without purification.

Step 3. Synthesis of(R)-6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amine

A mixture of 6-aminopyridine-2-carbohydrazide (450 mg, 2.96 mmol),6-methoxy-2,3,4,5-tetrahydropyridine (600 mg, 5.30 mmol) and AcOH (1.0mL, 17.5 mmol) in 2-pentanol (10.0 mL) was heated at reflux overnight.After cooling to rt, the mixture was basified with saturated NaHCO₃ andextracted with CH₂Cl₂ (3×30 mL). The combined organic layers were dried(Na₂SO₄), filtered, and concentrated under reduced pressure. Theresultant white solid was washed with a acetonitrile and hexanessuccessively to give(R)-6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amine(300 mg, 1.39 mmol, 47%) as a white solid: LC-MS, ES⁺: m/z 216.15[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.65 (dd, J=7.5, 0.9 Hz, 1H),7.57-7.50 (m, 1H), 6.51 (dd, J=8.2, 0.8 Hz, 1H), 5.08-4.96 (m, 1H),3.14-2.90 (comp, 3H), 2.44-2.32 (m, 1H), 1.48 (d, J=6.5 Hz, 3H).

Example 3 was prepared from(R)-6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amineand 3,4-dihydro-2,6-naphthyridine-2,7(1H)-dicarboxylate according to therepresentative procedure for amide formation with trimethylaluminum.

Example 4: Synthesis of ethyl(S)-7-((6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)carbamoyl)-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate

Example 4 was prepared from (R)-5-(bromomethyl)pyrrolidin-2-one usingthe sequence of reactions outlined for the preparation of(R)-7-((6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)carbamoyl)-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate.

Example 5: Synthesis of ethyl7-((6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)carbamoyl)-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate

Step 1. Synthesis of 5-methoxy-2,2-dimethyl-3,4-dihydro-2H-pyrrole

Trimethyloxonium tetrafluoroborate (19.6 g, 132.5 mmol) was addedportion wise to a solution of 5,5-dimethylpyrrolidin-2-one (10.0 g, 89.2mmol) in CH₂Cl₂ (100.0 mL) at 0° C. over 5 min. The reaction was stirredovernight at rt. The reaction was quenched with sat. NaHCO₃ and dilutedwith CH₂Cl₂. The layers were separated and the aqueous layer wasextracted with CH₂Cl₂ (3×100 mL). The combined organic layers werewashed with brine (100 mL), dried (Na₂SO₄) and filtered. AcOH (8.0 mL)was added to the filtrate, and the mixture was concentrated underreduced pressure. The crude product (11.0 g) was taken on to the nextstep without purification.

Step 2. Synthesis of6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amine

A mixture of 6-aminopyridine-2-carbohydrazide (8.4 g, 55.2 mmol),5-methoxy-2,2-dimethyl-3,4-dihydro-2H-pyrrole (11.0 g, 86.5 mmol) andAcOH (16.3 mL, 285.5 mmol) in 2-pentanol (40.0 mL) was heated at refluxovernight. After cooling to rt, the mixture was basified with saturatedNaHCO₃ and extracted with CH₂Cl₂ (3×100 mL). The combined organic layerswere dried (Na₂SO₄), filtered, and concentrated under reduced pressure.The resultant white solid was washed with a acetonitrile and hexanessuccessively to give6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amine(4.2 g, 18.3 mmol, 33%) as a white solid: LC-MS, ES⁺: m/z 230.15 [M+H]⁺;¹H NMR (400 MHz, Chloroform-d) δ 7.64 (dd, J=7.6, 0.9 Hz, 1H), 7.55 (t,J=7.8 Hz, 1H), 6.55 (dd, J=8.1, 0.9 Hz, 1H), 4.3 (brs, 2H), 3.05 (t,J=7.6 Hz, 2H), 2.60 (t, J=7.6 Hz, 2H), 1.77 (s, 6H).

Example 5 was prepared from6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amineand 3,4-dihydro-2,6-naphthyridine-2,7(1H)-dicarboxylate according to therepresentative procedure for amide formation with trimethylaluminum.

Example 6: Synthesis of tert-butyl7-((6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate

Step 1: Synthesis of tert-butyl7-hydroxy-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate

Formaldehyde (2.6 mL, 34.4 mmol of a 36% aqueous solution) was added toa solution of 4-(2-aminoethyl)-2-methoxyphenol, hydrochloride (1.0 g,4.9 mmol) in 1M HCl_((aq)) (4.9 mL) and the reaction was stirred at 50°C. for 6 h. The reaction was cooled to 0° C. and made basic with 50%aqueous NaOH (0.31 mL, 5.9 mmol). A solution of Boc₂O (5.7 mL, 24.55mmol) in THF (4.9 mL) was added dropwise at 0° C. The cold bath wasremoved, and the reaction was stirred at rt for 17 h. The reaction wasquenched with H₂O and diluted with MTBE (30 mL). The layers wereseparated and the aqueous layer was extracted with MTBE (2×30 mL). Thecombined organic layers were washed with brine, dried (MgSO₄), filtered,and concentrated under reduced pressure. The resultant orange oil waspurified by column chromatography eluting with hexanes/EtOAc (0%EtOAc→40% EtOAc) to afford tert-butyl7-hydroxy-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (570 mg,2.04 mmol, 41.6% yield) as a colorless gum: ¹H NMR (400 MHz,Chloroform-d) δ 6.65 (s, 1H), 6.60 (s, 1H), 5.48 (s, 1H), 4.45 (s, 2H),3.86 (s, 3H), 3.61 (t, J=5.9 Hz, 2H), 2.74 (t, J=5.9 Hz, 2H), 1.48 (s,9H).

Step 2: Synthesis of tert-butyl6-methoxy-7-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate

Trifluoromethanesulfonic anhydride (61.2 mL, 61.2 mmol, of a 1.0Msolution in CH₂Cl₂) was added dropwise to a solution of tert-butyl7-hydroxy-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (11.4 g,40.8 mmol) and 2,6-lutidine (14.3 mL, 13.1 g, 122 mmol) in CH₂Cl₂ (204mL) at 0° C. The cold bath was removed and the reaction was stirred atrt overnight. The reaction was diluted with CH₂Cl₂ (100 mL) and washedwith H₂O (150 mL×2) and brine (150 mL). The organic layer was dried(MgSO₄), filtered, and concentrated under reduced pressure. Theresultant yellow gum was purified by column chromatography eluting withhexanes/EtOAc (0% EtOAc→40% EtOAc) to afford tert-butyl6-methoxy-7-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate(12.5 g, 30.4 mmol, 75% yield) as a colorless solid: ¹H NMR (400 MHz,Chloroform-d) δ 6.95 (s, 1H), 6.78 (s, 1H), 4.50 (s, 2H), 3.89 (s, 3H),3.64 (t, J=5.8 Hz, 3H), 2.82 (t, J=5.9 Hz, 2H), 1.49 (s, 9H).

Step 3: Synthesis of 2-(tert-butyl) 7-methyl6-methoxy-3,4-dihydroisoquinoline-2,7(1H)-dicarboxylate

A mixture of6-methoxy-7-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate(6.0 g, 14.6 mmol), Pd(OAc)₂ (0.327 g, 1.46 mmol),1,3-bis(diphenylphosphino)propane (0.602 g, 1.46 mmol), and Et₃N (6.10mL, 43.8 mmol) in DMF (58.3 ml)/MeOH (38.9 ml) were stirred under aballoon of CO at 70° C. for 5 h. The reaction was quenched withH₂O/brine (200 m) and diluted with EtOAc (200 mL) and the layers wereseparated. The organic layer was washed with water/brine (2×100 mL). Theorganic layer was dried (MgSO₄), filtered, and concentrated underreduced pressure. The resultant brown oil was purified by columnchromatography eluting with hexanes/EtOAc (0% EtOAc→40% EtOAc) to afford2-(tert-butyl) 7-methyl6-methoxy-3,4-dihydroisoquinoline-2,7(1H)-dicarboxylate (4.3 g, 13.38mmol, 92% yield) as a colorless solid: ¹H NMR (400 MHz, Chloroform-d) δ7.57 (s, 1H), 6.72 (s, 1H), 4.51 (s, 2H), 3.88 (s, 3H), 3.87 (s, 3H),3.63 (t, J=6.1 Hz, 2H), 2.84 (t, J=6.1 Hz, 2H), 1.48 (s, 9H).

Step 4: Synthesis of2-(tert-butoxycarbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-7-carboxylicacid

LiOH.H₂O (1.8 g, 43.6 mmol) was added to a solution of 2-(tert-butyl)7-methyl 6-methoxy-3,4-dihydroisoquinoline-2,7(1H)-dicarboxylate (2.8 g,8.7 mmol) in THF (25 mL)/H₂O (8 mL) and the reaction was heated at 50°C. for 2 h. The reaction was cooled to rt then acidified with 10% citricacid (50 mL) and diluted with CH₂Cl₂ (50 mL). The layers were separatedand the aqueous layer was extracted with CH₂Cl₂ (2×50 mL). The combinedorganic layers were dried (MgSO₄), filtered, and concentrated underreduced pressure to afford2-(tert-butoxycarbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-7-carboxylicacid (2.68 g, 8.7 mmol, 100% yield) as a colorless amorphous solid: ¹HNMR (400 MHz, Chloroform-d) δ 10.67 (br s, 1H), 7.94 (s, 1H), 6.81 (s,1H), 4.55 (s, 2H), 4.06 (s, 3H), 3.66 (t, J=5.8 Hz, 2H), 2.88 (t, J=5.8Hz, 2H), 1.49 (s, 9H).

Step 5: Synthesis of tert-butyl7-((6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate

Representative Procedure for Amide Formation with Ghosez's Reagent.

Ghosez's Reagent (0.83 mL, 6.25 mmol) was added dropwise to a solutionof2-(tert-butoxycarbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-7-carboxylicacid (800 mg, 2.60 mmol) in CH₂Cl₂ (7.0 mL) at 0° C. The cold bath wasremoved and the reaction was stirred at rt for 1 h. The reaction wasconcentrated under reduced pressure and the resultant acid chloride wasdissolved in CH₂Cl₂ (7.0 mL) and cooled to 0° C.6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amine(597 mg, 2.60 mmol) was added, followed by pyridine (0.84 mL, 0.82 g,10.41 mmol). The reaction was stirred overnight, slowly warming to rt.The reaction was quenched with sat. NaHCO₃ and diluted with CH₂Cl₂. Thelayers were separated and the organic layer was washed with H₂O andbrine. The organic layer was dried (MgSO₄), filtered, and concentratedunder reduced pressure. The resultant pale yellow gum was purified bycolumn chromatography eluting with CH₂Cl₂/MeOH (0% MeOH→5% MeOH) toafford tert-butyl7-((6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(993 mg, 1.92 mmol, 74% yield) as a pale yellow solid.

Example 7: Synthesis ofN-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-methoxy-2-(3-methoxypropanoyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide

Step 1: Synthesis ofN-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-7-carboxamide,hydrochloride

Representative Procedure for Boc Deprotection.

4M HCl in dioxane (4.7 mL) was added to a solution of tert-butyl7-((6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(989 mg, 1.91 mmol) in MeOH (9.4 mL) and the reaction was stirred for 20min at 45° C. The reaction was concentrated under reduced pressure toafford crudeN-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-7-carboxamide,hydrochloride (937 mg, 1.91 mmol, 100% yield) as a tan solid: LC-MS,ES⁺: m/z 419.22 [M+H]⁺.

Step 2: Synthesis ofN-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-methoxy-2-(3-methoxypropanoyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide

Representative Procedure for Amide Formation Using Acid Chlorides.

3-methoxypropanoyl chloride (15 μl, 15 mg, 0.12 mmol) was added dropwiseto a solution ofN-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-7-carboxamide,hydrochloride (50 mg, 0.10 mmol) and Et₃N (71 μL, 52 mg, 0.51 mmol) inCH₂Cl₂ (1.0 mL) at 0° C. The cold bath was removed and the reaction wasstirred 1 h at rt. The reaction was quenched with sat. NaHCO₃ anddiluted with CH₂Cl₂. The layers were separated and the aqueous layer wasextracted with CH₂Cl₂ (2×). The combined organic layers were washed withbrine, dried (MgSO₄), filtered, and concentrated under reduced pressure.The resultant yellow gum was purified by column chromatography elutingwith CH₂Cl₂/MeOH (0% MeOH→7% MeOH) to affordN-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-methoxy-2-(3-methoxypropanoyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide(20.8 mg, 0.041 mmol, 41% yield) as a colorless amorphous solid.

Example 8: Synthesis ofN-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-(3-hydroxy-2,2-dimethylpropanoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-7-carboxamide

Step 1: Synthesis ofN-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-(3-hydroxy-2,2-dimethylpropanoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-7-carboxamide

Representative Procedure for HATU Coupling.

HATU (58.0 mg, 0.153 mmol) was added to a solution of3-hydroxy-2,2-dimethylpropanoic acid (12.0 mg, 0.102 mmol) in DMF (0.42mL) and the reaction was stirred for 5 min at rt.N-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-7-carboxamide,hydrochloride (50 mg, 0.102 mmol) was added, followed by DIPEA (89 μL,65.8 mg, 0.509 mmol), and the reaction was stirred for 2 h at rt. Thereaction was quenched with sat. NaHCO₃ and diluted with CH₂Cl₂. Thelayers were separated and the aqueous layer was extracted with CH₂Cl₂(2×). The combined organic layers were washed with brine, dried (MgSO₄),filtered, and concentrated under reduced pressure. The resultant whitesolid was purified by column chromatography eluting with CH₂Cl₂/MeOH (0%MeOH→7% MeOH) to affordN-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-(3-hydroxy-2,2-dimethylpropanoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-7-carboxamide(45.7 mg, 0.088 mmol, 87% yield) as a colorless amorphous solid.

(S)—N-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-(3-hydroxybutanoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-7-carboxamide,(S)—N-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-(2-hydroxy-4-methylpentanoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-7-carboxamide,andN-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-(2-hydroxy-2-methylpropanoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-7-carboxamidewere prepared fromN-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-7-carboxamide,hydrochloride according to the representative procedure for HATUcoupling.

Example 9: Synthesis of ethyl7-((6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate

Step 1: Synthesis of ethyl7-((6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate

Representative Procedure for Carbamate Formation.

Ethyl chloroformate (12 μl, 13 mg, 0.12 mmol) was added dropwise to asolution ofN-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-7-carboxamide,hydrochloride (50 mg, 0.10 mmol) and Et₃N (71 μL, 52 mg, 0.51 mmol) inCH₂Cl₂ (1.0 mL) at 0° C. The cold bath was removed and the reaction wasstirred 1 h at rt. The reaction was quenched with sat. NaHCO₃ anddiluted with CH₂Cl₂. The layers were separated and the aqueous layer wasextracted with CH₂Cl₂ (2×). The combined organic layers were washed withbrine, dried (MgSO₄), filtered, and concentrated under reduced pressure.The resultant yellow gum was purified by column chromatography elutingwith CH₂Cl₂/MeOH (0% MeOH→7% MeOH) to afford ethyl7-((6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(15.7 mg, 0.032 mmol, 27% yield) as a colorless amorphous solid.

Ethyl6-methoxy-7-((6-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylatewas prepared in analogous fashion to example 9, starting from2-(tert-butoxycarbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-7-carboxylicacid and6-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)pyridin-2-amine.

Ethyl(R)-6-methoxy-7-((6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylatewas prepared in analogous fashion to example 9, starting from2-(tert-butoxycarbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-7-carboxylicacid and(R)-6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amine.

Ethyl(S)-6-methoxy-7-((6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylatewas prepared in analogous fashion to example 9, starting from2-(tert-butoxycarbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-7-carboxylicacid and(S)-6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amine.

Ethyl7-((6-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylatewas prepared in analogous fashion to example 9, starting from2-(tert-butoxycarbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-7-carboxylicacid and6-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amine.

Example 10: Synthesis of ethyl7-((6-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)carbamoyl)-6-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate

Step 1. Synthesis of 7-bromo-6-fluoro-1,2,3,4-tetrahydroisoquinoline

Lithium triethylborohydride (74.0 mL, 74.0 mmol of a 1.0M solution inTHF) was added dropwise to a solution of 7-bromo-6-fluoroisoquinoline(7.6 g, 33.6 mmol) in THF (210 mL) at 0° C. The cold bath was removed,and the reaction was stirred at rt overnight.

The reaction was cooled to 0° C. and quenched dropwise with MeOH untilgas evolution ceased. The mixture was diluted with 1M HCl and MTBE. Thelayers were separated and the organic layer was extracted with 1M HCl(2×). The combined aqueous layers were washed with MTBE (3×). Theaqueous layer was made basic (pH 14) with 50% NaOH, then extracted(5×100 mL) with DCM. The combined organic layers were dried (Na₂SO₄),filtered, and concentrated under reduced pressure to afford crude7-bromo-6-fluoro-1,2,3,4-tetrahydroisoquinoline (6.4 g) as a yellow oil:¹H NMR (400 MHz, Chloroform-d) δ 7.18 (d, J=6.9 Hz, 1H), 6.85 (d, J=9.3Hz, 1H), 3.94 (s, 2H), 3.10 (t, J=6.1 Hz, 2H), 2.73 (t, J=6.0 Hz, 2H).

Step 2. Synthesis of ethyl7-bromo-6-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate

Ethyl chloroformate (1.1 mL, 1.25 g, 11.5 mmol) was added to a solutionof 7-bromo-6-fluoro-1,2,3,4-tetrahydroisoquinoline (2.2 g, 9.6 mmol) andEt₃N (2.6 mL, 1.9 g, 19.2 mmol) in CH₂Cl₂ (20 mL) at 0° C. The cold bathwas removed and the reaction stirred for 2 h at rt. The reaction wasquenched with H₂O and the layers were separated. The organic layer waswashed with brine, dried (Na₂SO₄), filtered, and concentrated underreduced pressure to afford ethyl7-bromo-6-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.5 g, 5.08mmol, 52.9%) as a yellow oil which was used in the next step withoutfurther purification: LC-MS, ES⁺: m/z 301.90 [M+H]⁺.

Step 3. Synthesis of diethyl6-fluoro-3,4-dihydroisoquinoline-2,7(1H)-dicarboxylate

A mixture of ethyl7-bromo-6-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.5 g, 5.0mmol), Pd(OAc)₂ (113 mg, 0.5 mmol), 1,3-bis(diphenylphosphino)propane(412 mg, 1.0 mmol), and Et₃N (1.38 mL, 1.0 g, 10.0 mmol) in DMF (20.0mL)/EtOH (7.0 mL) were stirred under a balloon of CO at 80° C. for 24 h.The reaction was cooled to rt, quenched with H₂O (30 mL), and dilutedwith EtOAc (40 mL). The layers were separated and the aqueous layer wasextracted with EtOAc (3×30 mL). The combined organic layers were washedwith brine (3×30 mL), dried (Na₂SO₄), filtered, and concentrated underreduced pressure. The resultant residue was purified by columnchromatography eluting with hexanes/EtOAc (0% EtOAc→20% EtOAc) to afforddiethyl 6-fluoro-3,4-dihydroisoquinoline-2,7(1H)-dicarboxylate (0.9 g,3.05 mmol, 61% yield) as a yellow oil: LC-MS, ES⁺: m/z 296.10 [M+H]⁺.

Step 4. Synthesis of2-(ethoxycarbonyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline-7-carboxylicacid

diethyl 6-fluoro-3,4-dihydroisoquinoline-2,7(1H)-dicarboxylate (0.9 g,3.0 mmol) was added to a solution of LiOH (1.4 g, 60 mmol) in THF (15.0mL)/H₂O (15.0 mL) and the reaction was stirred overnight at rt. The pHwas adjusted to −4 with 1M HCl_((aq)). The aqueous layer was extractedwith EtOAc (3×30 mL). The combined organic layers were dried (Na₂SO₄),filtered, and concentrated under reduced pressure to afford2-(ethoxycarbonyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline-7-carboxylicacid (600 mg, 2.25 mmol, 75%) as a yellow oil: LC-MS, ES⁺: m/z 268.00[M+H]⁺.

Example 10 was prepared from2-(ethoxycarbonyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline-7-carboxylicacid and6-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amineaccording to the representative procedure for amide formation withGhosez's reagent.

Ethyl6-fluoro-7-((6-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylatewas prepared from2-(ethoxycarbonyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline-7-carboxylicacid and6-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)pyridin-2-amineaccording to the representative procedure for amide formation withGhosez's reagent.

Ethyl7-((6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)carbamoyl)-6-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylatewas prepared from2-(ethoxycarbonyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline-7-carboxylicacid and6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amineaccording to the representative procedure for amide formation withGhosez's reagent.

Ethyl(R)-6-fluoro-7-((6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylatewas prepared from2-(ethoxycarbonyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline-7-carboxylicacid and(R)-6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amineaccording to the representative procedure for amide formation withGhosez's reagent.

Ethyl(S)-6-fluoro-7-((6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylatewas prepared from2-(ethoxycarbonyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline-7-carboxylicacid and(S)-6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amineaccording to the representative procedure for amide formation withGhosez's reagent.

Characterization data for examples are shown in Table 6.

TABLE 6 LC-MS [M + H]⁺ unless Ex- otherwise ample Structure noted ¹H-NMR1

477 ¹H NMR (400 MHz, DMSO-d₆) δ 10.68 (s, 1H), 8.25 (d, J = 8.2 Hz, 1H),8.00 (t, J = 8.0 Hz, 1H), 7.87 (dd, J = 7.8, 0.9 Hz, 1H), 7.68 (s, 1H),7.08 (s, 1H), 4.56 (s, 2H), 4.49 (t, J = 6.0 Hz, 2H), 4.10 (q, J = 7.1Hz, 2H), 3.96 (s, 3H), 3.62 (t, J = 6.0 Hz, 2H), 2.93 (t, J = 6.4 Hz,2H), 2.88 (t, J = 6.0 Hz, 2H), 2.06-1.80 (m, 4H), 1.22 (t, J = 7.1 Hz,3H). 2

491 ¹H NMR (400 MHz, DMSO-d₆) δ 10.57 (s, 1H), 8.37 (d, J = 8.2 Hz, 1H),8.04 (t, J = 8.0 Hz, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.87 (s, 1H), 7.16(s, 1H), 4.57 (s, 2H), 4.10 (q, J = 7.1 Hz, 2H), 4.04 (s, 3H), 3.63 (t,J = 5.9 Hz, 2H), 3.06 (t, J = 7.5 Hz, 2H), 2.89 (t, J = 5.9 Hz, 2H),2.64 (t, J = 7.5 Hz, 2H), 1.79 (s, 6H), 1.22 (t, J = 7.1 Hz, 3H). 3

477 ¹H NMR (400 MHz, Chloroform-d) δ 10.37 (s, 1H), 8.47 (d, J = 8.2 Hz,1H), 8.10-8.08 (m, 2H), 7.89 (t, J = 7.6 Hz, 1H), 6.85 (s, 1H), 5.09 (m,1H), 4.67 (s, 2H), 4.22 (q, J = 7.1 Hz, 2H), 4.08 (s, 3H), 3.75 (t, J =7.1 Hz, 2H), 3.18- 3.09 (m, 3H), 2.94 (t, J = 5.8 Hz, 2H), 2.48 (m, 1H),1.60 (s, 3H),1.33 (t, J = 7.1 Hz, 3H). 4

477 ¹H NMR (400 MHz, Chloroform-d) δ 10.37 (s, 1H), 8.46 (d, J = 8.2 Hz,1H), 8.07 (d, J = 7.6 Hz, 2H), 7.88 (t, J = 8.0 Hz, 1H), 6.84 (s, 1H),5.07 (m, 1H), 4.67 (s, 2H), 4.22 (q, J = 7.1 Hz, 2H), 4.08 (s, 3H), 3.75(t, J = 6.0 Hz, 2H), 3.15-3.08 (m, 3H), 2.93 (t, J = 5.9 Hz, 2H), 2.48(m, 1H), 1.64 (d, J = 6.4 Hz, 3H), 1.33 (t, J = 7.1 Hz, 3H). 5

434 ¹H NMR (400 MHz, Methanol-d₄) δ 8.54 (s, 1H), 8.50 (d, J = 8.0 Hz,1H), 8.12-8.03 (m, 2H), 7.97 (d, J = 7.6 Hz, 1H), 4.79 (s, 2H), 4.70 (t,J = 7.2 Hz, 2H), 4.22 (q, J = 7.1 Hz, 2H), 3.81 (t, J = 5.7 Hz, 2H),3.19 (t, J = 7.7 Hz, 2H), 3.02-2.92 (m, 4H), 1.33 (t, J = 7.1 Hz, 3H). 6

448 ¹H NMR (400 MHz, Chloroform-d) δ 10.39 (s, 1H), 8.49-8.43 (m, 2H),8.10-8.07 (m, 2H), 7.91 (t, J = 7.9 Hz, 1H), 4.77 (s, 2H), 4.60 (s, 2H),4.24 (q, J = 7.1 Hz, 2H), 3.81 (t, J = 5.8 Hz, 2H), 3.13 (s, 2H), 2.98(t, J = 5.6 Hz, 2H), 2.11 (m, 2H), 2.01 (m, 2H), 1.34 (t, J = 7.1 Hz,3H). 7

448 ¹H NMR (400 MHz, Chloroform-d) δ 10.43 (s, 1H), 8.54-8.45 (m, 2H),8.16-8.08 (m, 2H), 7.95 (t, J = 7.9 Hz, 1H), 5.39-5.23 (m, 4H), 4.78 (s,2H), 4.25 (q, J = 7.1 Hz, 2H), 3.82 (t, J = 5.7 Hz, 2H), 3.25 (s, 2H),3.15 (s, 1H), 2.99 (t, J = 5.7 Hz, 2H), 2.54 (m, 1H), 1.34 (t, J = 7.1Hz, 3H). 8

451 ¹H NMR (400 MHz, Chloroform-d) δ 9.07 (d, J = 15.9 Hz, 1H), 8.39 (d,J = 8.2 Hz, 1H), 8.09 (d, J = 7.6 Hz, 1H), 7.98 (d, J = 7.8 Hz, 1H),7.90 (t, J = 8.0 Hz, 1H), 7.02 (d, J = 12.6 Hz, 1H), 4.70 (s, 2H), 4.46(t, J = 7.2 Hz, 2H), 4.22 (q, J = 7.2 Hz, 2H), 3.75 (t, J = 6.1 Hz, 2H),3.06 (t, J = 7.6 Hz, 2H), 2.94 (t, J = 6.0 Hz, 2H), 2.85 (m, 2H), 1.32(t, J = 7.1 Hz, 3H). 9

465 ¹H NMR (400 MHz, Chloroform-d) δ 9.06 (d, J = 15.4 Hz, 1H), 8.42 (d,J = 8.3 Hz, 1H), 8.08 (d, J = 7.7 Hz, 1H), 7.97 (d, J = 7.8 Hz, 1H),7.92 (t, J = 8.0 Hz, 1H), 7.02 (d, J = 12.6 Hz, 1H), 4.70 (s, 2H), 4.54(t, J = 5.9 Hz, 2H), 4.22 (q, J = 7.1 Hz, 2H), 3.75 (t, J = 5.9 Hz, 2H),3.50 (m, 2H), 3.15 (t, J = 6.3 Hz, 2H), 2.94 (t, J = 6.0 Hz, 2H), 2.09(m, 2H), 2.01 (m, 2H), 1.33 (t, J = 7.1 Hz, 3H). 10

462 ¹H NMR (400 MHz, Chloroform-d) δ 10.48 (s, 1H), 8.48 (d, J = 6.8 Hz,2H), 8.10 (d, J = 8.3 Hz, 2H), 7.93 (t, J = 7.9 Hz, 1H), 4.78 (s, 2H),4.25 (q, J = 7.1 Hz, 2H), 3.81 (t, J = 5.7 Hz, 2H), 3.16 (s, 2H), 2.98(t, J = 5.7 Hz, 2H), 2.69 (s, 2H), 1.86 (s, 6H), 1.34 (t, J = 7.1 Hz,3H). 11

479 ¹H NMR (400 MHz, Chloroform-d) δ 9.17 (d, J = 17.3 Hz, 1H), 8.42 (d,J = 8.2 Hz, 1H), 8.11 (d, J = 7.7 Hz, 1H), 8.02 (d, J = 7.9 Hz, 1H),7.92 (t, J = 8.0 Hz, 1H),7.03 (d, J = 12.9 Hz, 1H), 4.71 (s, 2H), 4.23(q, J = 7.1 Hz, 2H), 3.76 (t, J = 5.9 Hz, 2H), 3.13 (t, J = 6.8 Hz, 2H),2.94 (t, J = 5.8 Hz, 2H), 2.68 (t, J = 7.2 Hz, 2H), 1.82 (s, 6H), 1.33(t, J = 7.1 Hz, 4H). 12

465 ¹H NMR (400 MHz, Chloroform-d) δ 9.10 (d, J = 16.6 Hz, 1H), 8.40 (d,J = 8.2 Hz, 1H), 8.11 (d, J = 7.6 Hz, 1H), 8.00 (d, J = 7.8 Hz, 1H),7.91 (t, J = 8.0 Hz, 1H), 7.03 (d, J = 12.7 Hz, 1H), 5.06 (m, 1H), 4.71(s, 2H), 4.23 (q, J = 7.1 Hz, 2H), 3.76 (t, J = 5.2 Hz, 2H), 3.13 (s,0H), 3.05 (t, J = 10.0 Hz, 3H), 2.94 (t, J = 5.9 Hz, 2H), 2.46 (d, J =10.5 Hz, 1H), 1.58 (d, J = 6.2 Hz, 3H), 1.33 (t, J = 7.1 Hz, 3H). 13

465 ¹H NMR (400 MHz, Chloroform-d) δ 9.10 (d, J = 16.5 Hz, 1H), 8.39 (d,J = 8.3 Hz, 1H), 8.10 (d, J = 7.7 Hz, 1H), 7.99 (d, J = 7.8 Hz, 1H),7.90 (t, J = 8.0 Hz, 1H), 7.02 (d, J = 12.8 Hz, 1H), 5.05 (m, 1H), 4.70(s, 2H), 4.22 (q, J = 7.1 Hz, 2H), 3.75 (t, J = 5.9 Hz, 2H), 3.09-2.99(m, 3H), 2.94 (t, J = 5.6 Hz, 2H), 2.45 (m, 1H), 1.57 (d, J = 6.4 Hz,3H), 1.32 (t, J = 7.1 Hz, 3H). 14

519 ¹H NMR (400 MHz, DMSO-d₆) δ 10.55 (s, 1H), 8.33 (dd, J = 8.3, 0.9Hz, 1H), 8.01 (t, J = 8.0 Hz, 1H), 7.89 (dd, J = 7.7, 0.9 Hz, 1H), 7.86(s, 1H), 7.14 (s, 1H), 4.52 (s, 2H), 4.03 (s, 3H), 3.57 (t, J = 5.8 Hz,2H), 2.98 (dd, J = 8.1, 7.0 Hz, 2H), 2.87 (t, J = 5.9 Hz, 2H), 2.61 (t,J = 7.5 Hz, 2H), 1.76 (s, 6H), 1.43 (s, 9H). 15

448 ¹H NMR (400 MHz, Chloroform-d) δ 10.41 (s, 1H), 8.47-8.45 (m, 2H),8.13-8.11 (m, 2H), 7.93 (t, J = 7.9 Hz, 1H), 5.20 (m, 1H), 4.78 (s, 2H),4.25 (q, J = 7.1 Hz, 2H), 3.82 (t, J = 5.6 Hz, 2H), 3.17-3.08 (m, 3H),2.99 (t, J = 6.0 Hz, 2H), 2.48 (m, 1H), 1.59 (d, J = 6.3 Hz, 3H), 1.34(t, J = 7.1 Hz, 3H). 16

505 ¹H NMR (400 MHz, DMSO-d₆) δ 10.56 (d, J = 4.7 Hz, 1H), 8.38-8.30 (m,1H), 8.01 (td, J = 7.9, 1.8 Hz, 1H), 7.92 (d, J = 11.7 Hz, 1H), 7.88 (d,J = 4.6 Hz, 1H), 7.16 (d, J = 2.9 Hz, 1H), 4.71 (s, 1H), 4.62 (s, 1H),4.04 (d, J = 1.5 Hz, 3H), 3.69 (dt, J = 9.1, 5.9 Hz, 2H), 3.58 (td, J =6.5, 3.0 Hz, 2H), 3.22 (d, J = 6.5 Hz, 3H), 3.02-2.91 (comp, 3H), 2.85(t, J = 6.0 Hz, 1H), 2.68 (dt, J = 8.0, 4.0 Hz, 2H), 2.61 (t, J = 7.5Hz, 2H), 1.76 (s, 6H). 17

519 ¹H NMR (400 MHz, DMSO-d₆) δ 10.55 (s, 1H), 8.33 (dd, J = 8.3, 0.9Hz, 1H), 8.01 (t, J = 8.0 Hz, 1H), 7.92 (s, 1H), 7.89 (dd, J = 7.7, 0.9Hz, 1H), 7.14 (s, 1H), 4.72 (s, 2H), 4.58 (t, J = 5.8 Hz, 1H), 4.03 (s,3H), 3.79 (t, J = 5.9 Hz, 2H), 3.47 (d, J = 5.9 Hz, 2H), 2.98 (dd, J =8.1, 7.0 Hz, 2H), 2.89 (t, J = 5.9 Hz, 2H), 2.61 (t, J = 7.5 Hz, 2H),1.76 (s, 6H), 1.19 (s, 6H). 18

505 ¹H NMR (400 MHz, DMSO-d₆) δ 10.56 (d, J = 4.3 Hz, 1H), 8.38-8.30 (m,1H), 8.01 (td, J = 8.0, 2.1 Hz, 1H), 7.94-7.89 (m, 1H), 7.89- 7.85 (m,1H), 7.16 (d, J = 3.4 Hz, 1H), 4.80- 4.56 (comp, 3H), 4.07-3.99 (comp,4H), 3.76- 3.65 (m, 2H), 3.03-2.90 (comp, 3H), 2.85 (t, J = 6.0 Hz, 1H),2.64-2.54 (comp, 3H), 2.41 (ddd, J = 15.0, 9.6, 5.4 Hz, 1H), 1.76 (s,6H), 1.11 (dd, J = 8.2, 6.2 Hz, 3H). 19

533 ¹H NMR (400 MHz, DMSO-d₆) δ 10.56 (d, J = 3.1 Hz, 1H), 8.33 (dd, J =8.3, 0.9 Hz, 1H), 8.00 (t, J = 8.0 Hz, 1H), 7.90 (t, J = 1.5 Hz, 1H),7.88 (s, 1H), 7.16 (s, 1H), 4.88 (dd, J = 45.6, 7.2 Hz, 1H), 4.81-4.52(m, 2H), 4.48- 4.38 (m, 1H), 4.04 (s, 3H), 3.82-3.60 (comp, 2H),3.01-2.93 (comp, 3H), 2.87 (t, J = 6.0 Hz, 1H), 2.61 (t, J = 7.5 Hz,2H), 1.84-1.71 (m, 1 H), 1.76 (s, 6H), 1.57-1.20 (comp, 2H), 0.97- 0.82(m, 6H). 20

505 ¹H NMR (400 MHz, DMSO-d₆) δ 10.56 (s, 1H), 8.33 (dd, J = 8.3, 0.9Hz, 1H), 8.01 (t, J = 8.0 Hz, 1H), 7.89 (dd, J = 7.7, 0.9 Hz, 1H), 7.86(s, 1H), 7.14 (s, 1H), 5.50 (s, 1H), 5.24- 4.99 (m, 1H), 4.74-4.54 (m,1H), 4.22-4.08 (m, 1H), 4.04 (s, 3H), 3.85-3.61 (m, 1H), 2.98 (dd, J =8.1, 7.0 Hz, 2H), 2.91 (br s, 2H), 2.61 (t, J = 7.5 Hz, 2H), 1.76 (s,6H), 1.34 (s, 6H). 21

463 ¹H NMR (400 MHz, Methanol-d₄) δ 8.39 (d, J = 8.2 Hz, 1H), 7.99 (t, J= 7.9 Hz, 1H), 7.91 (d, J = 4.7 Hz, 2H), 7.08 (s, 1H), 4.64 (s, 2H),4.57 (t, J = 7.2 Hz, 2H), 4.21 (q, J = 7.1 Hz, 2H), 4.10 (s, 3H), 3.74(s, 2H), 3.05 (m, 2H), 2.98-2.86 (m, 4H), 1.32 (t, J = 7.1 Hz, 3H).AssayHTRF® KinEASE™ Assay

ASK1 was purchased from Thermofisher (Catalogue #PV4011), ATP waspurchased from Sigma (Catalogue #A7699), HTRF® KinEASE™ Assay System wasobtained from Cisbio (Bedford, Mass.). ½ Area plate was purchased fromPerkin Elmer (Catalogue ##6005560). HTRF® KinEASE™-STK is a genericmethod for measuring serine/threonine kinase activities using atime-resolved fluorescence resonance energy transfer (TR-FRET)immunoassay. The IC₅₀ value for each compound was determined in thepresence of compound (various concentration from 0 to 10 μM) and a fixedamount of ATP and peptide substrates. The test compound, 1 μM STK3peptide substrate, and 5 μM of ASK1 kinase are incubated with kinasereaction buffer containing 50 mM HEPES Ph 7.5, 0.01% BRIJ-35, 10 mMMgCl₂, and 1 mM EGTA for 30 minutes. 100 μM ATP is added to start kinasereaction and incubated for 3 hours. The STK3-antibody labeled withEu³⁺-Cryptate and 125 nM streptavidin-XL665 are mixed in a singleaddition with stop reagents provided by the Cisbio kit used to stop thekinase reaction. Fluorescence is detected using an Envision Multilabeled2014 reader from PerkinElmer. The Fluorescence is measured at 615 nm(Cryptate) and 665 nm (XL665) and a ratio of 665 nm/615 nm is calculatedfor each well. The resulting TR-FRET is proportional to thephosphorylation level. Staurosporine was used as the positive control.IC₅₀ was determined by Xlfit 5.3.

By using above method, the inhibition of ASK1 was evaluated for thecompounds of Formula (I). The results are shown in Table 7. Examplenumbers correspond to those in Table 6. IC₅₀ ranges are as follows:A=IC₅₀<1.25 nM; B=1.25 nM<IC₅₀<10 nM; C=10 nM<IC₅₀<100 nM; D=100nM<IC₅₀<1 μM; E=IC₅₀>1 μM.

TABLE 7 Example IC50 (nM) 1 C 2 A 3 A 4 B 5 C 6 E 7 C 8 D 9 E 10 B 11 B12 B 13 C 14 B 15 B 16 A 17 A 18 A 19 A 20 A 21 B

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

What is claimed:
 1. A compound represented by Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: A isheterocycloalkyl or heteroaryl, wherein the heterocycloalkyl orheteroaryl is optionally substituted; X¹ is CR⁶; X² is CR⁶; X³ is CR⁷ orN; R² is H, halogen, NO₂, CN, C₁-C₈ alkyl, arylalkyl, heteroarylalkyl,C₂-C₈ alkenyl, C₂-C₈ alkynyl, NR⁴R⁵, NR⁴C(O)R⁵, NR⁴S(O)₂R⁵, S(O)₂NR⁴R⁵,C₃-C₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, aryl, orheteroaryl, wherein the C₁-C₈ alkyl, arylalkyl, heteroarylalkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, 3- to 8-memberedheterocycloalkyl, aryl, or heteroaryl is optionally substituted; R³ isH, C₁-C₈ alkyl, arylalkyl, heteroarylalkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, C(O)R⁴, C(O)NR⁴R⁵, C(O)OR⁴, S(O)₂R⁴, C₃-C₈ cycloalkyl, 3- to8-membered heterocycloalkyl, aryl, or heteroaryl, wherein the C₁-C₈alkyl, arylalkyl, heteroarylalkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈cycloalkyl, 3- to 8-membered heterocycloalkyl, aryl, or heteroaryl isoptionally substituted; R⁴ is H, C₁-C₈ alkyl, arylalkyl,heteroarylalkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl,heterocycloalkyl, aryl, or heteroaryl, wherein the C₁-C₈ alkyl,arylalkyl, heteroarylalkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, CN, CF₃, alkyl, C(O)heterocycloalkyl,NHalkyl, N(alkyl)₂, NHC(O)alkyl, NHC(O)aryl, NHC(O)heteroaryl, OH,Oalkyl, ═O, C₃-C₈ cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R⁵is H, C₁-C₈ alkyl, arylalkyl, heteroarylalkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, C₃-C₈ cycloalkyl, heterocycloalkyl, aryl, or heteroaryl,wherein the C₁-C₈ alkyl, arylalkyl, heteroarylalkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, heterocycloalkyl, aryl, or heteroarylis optionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, CN, CF₃, alkyl,C(O)heterocycloalkyl, NHalkyl, N(alkyl)₂, NHC(O)alkyl, NHC(O)aryl,NHC(O)heteroaryl, OH, Oalkyl, ═O, C₃-C₈ cycloalkyl, heterocycloalkyl,aryl, and heteroaryl; or R⁴ and R⁵, taken together with the nitrogenatom to which they are attached, form a heterocycloalkyl, wherein theheterocycloalkyl is optionally substituted; R⁶ is H, halogen, NO₂, CN,C₁-C₈ alkyl, arylalkyl, heteroarylalkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,NR⁴R⁵, NR⁴C(O)R⁵, NR⁴S(O)₂R⁵, S(O)₂NR⁴R⁵, C₃-C₈ cycloalkyl, 3- to8-membered heterocycloalkyl, aryl, or heteroaryl, wherein the C₁-C₈alkyl, arylalkyl, heteroarylalkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈cycloalkyl, 3- to 8-membered heterocycloalkyl, aryl, or heteroaryl isoptionally substituted; R⁷ is H, halogen, C₁-C₈ alkyl, or OC₁-C₈ alkyl,wherein the C₁-C₈ alkyl or OC₁-C₈ alkyl is optionally substituted; R⁸ isH, C₁-C₈ alkyl, or OH, wherein the C₁-C₈ alkyl is optionallysubstituted; R⁹ is H, C₁-C₈ alkyl, or OH, wherein the C₁-C₈ alkyl isoptionally substituted; or R⁸ and R⁹, taken together with the carbonatom to which they are attached, form C(O), a spirocyclic C₃-C₈cycloalkyl, or a spirocyclic 3- to 8-membered heterocycloalkyl; R¹⁰ isH, halogen, or C₁-C₈ alkyl, wherein the C₁-C₈ alkyl is optionallysubstituted; R¹¹ is H, halogen, or C₁-C₈ alkyl, wherein the C₁-C₈ alkylis optionally substituted; and n is 0, 1, or 2; wherein each optionallysubstituted group of A, R², R³, the heterocycloalkyl formed by R⁴ andR⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ is optionally and independentlysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of D, F, C₁, Br, I, CN, NO₂, C₁-C₁₂ alkyl, C₁-C₁₂haloalkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ haloalkenyl, C₂-C₁₂ alkynyl, C₂-C₁₂haloalkynyl, NH₂, NHC(O)OC(CH₃)₃, NHC(O)OCH₂Ph,NHC(O)OCH₂-(9-fluorenyl), N₃, OH, Oalkyl, OCH₂OCH₃, OC(O)CH₃,OC(O)CH₂Ph, OSi(CH₃)₃, OSi(CH₂CH₃)₃, Salkyl, and C₃-C₁₂ halocycloalkyl.2. The compound of claim 1, wherein the compound is represented byFormula II:

or a pharmaceutically acceptable salt thereof.
 3. The compound of claim1, wherein the compound is represented by Formula III:

or a pharmaceutically acceptable salt thereof.
 4. The compound of claim1, wherein the compound is represented by Formula V:

or a pharmaceutically acceptable salt thereof.
 5. The compound of claim1, wherein the compound is represented by Formula VI, Formula VII,Formula VIII, Formula IX, or Formula X:

or a pharmaceutically acceptable salt thereof.
 6. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein

is selected from the group consisting of:

wherein each of the above shown groups is optionally substituted.
 7. Thecompound of claim 1, wherein the compound is selected from the compoundsset forth in Table 1: TABLE 1 compound Structure 1

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or a pharmaceutically acceptable salt thereof.
 8. The compound of claim1, wherein the compound is selected from the compounds set forth inTable 2: TABLE 2 compound Structure  97

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or a pharmaceutically acceptable salt thereof.
 9. The compound of claim1, wherein the compound is selected from the compounds set forth inTable 3: TABLE 3 compound Structure 193

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or a pharmaceutically acceptable salt thereof.
 10. The compound of claim1, wherein the compound is selected from the compounds set forth inTable 4: TABLE 4 compound Structure 289

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or a pharmaceutically acceptable salt thereof.
 11. The compound of claim1, wherein the compound is selected from the compounds set forth inTable 5: TABLE 5 compound Structure 385

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or a pharmaceutically acceptable salt thereof.
 12. The compound of claim1, wherein the compound is selected from the compounds set forth inTable 6: TABLE 6 Compound Structure 1

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or a pharmaceutically acceptable salt thereof.
 13. A pharmaceuticalcomposition comprising the compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipient orcarrier.
 14. A compound selected from the compounds set forth in thetable below: Compound Structure 4

36

68

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452

or a pharmaceutically acceptable salt thereof.